JPH07508747A - Pharmaceutical heterocyclic compounds - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Pharmaceutical heterocyclic compounds The present invention provides novel compounds, methods for producing the compounds, and pharmaceutical compositions containing the compounds. and the use of said compounds and compositions in medicine.

European Patent Application Publication No. 0008203.0139421.0155845.01 77353.0193256.0207581.0208420.030622 8 and International Patent Application Publication No. WO9101337, there are Thiacyridiendione derivatives are disclosed that are described as having hemoactivity. . Chemical and Pharmaceutical Bulletin (Chew, Pha) rm.

Bull, ) 1982.30 (10) 3580-3600, hypoglycemic activity and Certain thiacylidienedione derivatives have been disclosed that have hypolipidemic and hypolipidemic activity. .

International patent application publication number W091/19702 contains formulas (A) and (B): and Beauty [In the formula, A is n is 0 or 1.

m is 0.1 or 2: 1--- represents bond or non-bond.

R is (C, ~Cs) alkyl, (C3~Ct) chloroalkyl, (C, ~C@ ) alkenyl, (C1-Cs) alkynyl, phenyl, (Ct-Cm) phenyl Alkyl, (C2-Cm)alkanoyl, or (C+-C,)alkyl, tri- Fluoromethyl, hydroxy, (C1-Cs)alkoxy, fluoro or carbon one of these groups mono- or di-substituted with Rolo; W is OS CO,, CH2, CHOH or -CH=CH-: X is S, O, NR2 , -CH=CH-1-CH=N-1 is -N=CH-.

R2 is hydrogen, (01-C,)alkyl, phenyl or benzyl; Y is , CH or N; Z is H1 amino, (C0-C7) alkyl, (C8-C7) chloroalkyl, Phenyl, or (C+~C,)alkyl, trifluoromethyl, (01~C, )Alkoxy, phenyl, phenokine, benzyl, benzyloxy, and fluoro or phenyl mono- or di-substituted with chloro.

Zl is hydrogen or (C,-C,)alkyl.

Xl is 0, S, SO or SO2.

Yl is hydroxy, (C1-C3) alkoxy, phenoxy, benzyloxy , amino, (C, ~C4) alkanoylamino, (C1 ~ C4) alkanesulfo Nyl-amino, benzenesulfonylamino, naphthalenesulfonylamino, di[ (C1~Cs)alkylcoaminosulfonylamino, or (C+~CS)alkylcoaminosulfonylamino Kyl, trifluoromethyl, hydroxy, (01-Cx)alkoxy, fluoro or one of these groups mono- or di-substituted with chloro. ], when Yl is hydroxy, its pharmaceutically acceptable Cationic salts: and when the compound contains a basic nitrogen atom, its pharmaceutically acceptable Acid addition salts are disclosed.

The compound represented by formula (A) is useful as a hypoglycemic agent and a low-cholesterol agent. It is disclosed that.

Now, surprisingly, certain new compounds that are structurally different from the above-mentioned compounds appear to be particularly good. It exhibits good hypoglycemic activity and is therefore useful in the treatment and/or prevention of hyperglycemia. and has been found to be particularly useful in the treatment of type II diabetes.

These compounds may be used to treat other diseases including hyperglycemia and hypertension and/or has also been shown to be useful for prevention. They are also associated with cardiovascular disease, especially It has also been shown to be useful in the treatment and/or prevention of telosclerosis. . Additionally, these compounds have been shown to be useful in the treatment of certain eating disorders, particularly anorexia nervosa. which under-eating-related disorders, as well as obesity and Overeating (ov), such as anorexia bulimia Appetite and feeding in patients suffering from disorders associated with er-eating It appears to be useful in regulating behavior.

Therefore, the present invention provides formula (1) %formula%() [In the formula, A1 represents a substituted or unsubstituted aromatic heterocyclic group; A2 optionally represents three groups; Represents a benzene ring that may have a substituent.

A3 represents a group represented by the formula (CHz)-CH(OR')- as tEL, cocote, R' is substituted or unsubstituted alkyl, aryl, aralkyl or alkyl group represents rubonyl, m represents an integer in the range of 1 to 5, or A represents the formula - (CH2), -CH=C(OR')-, where R1 and and m are the same as defined above.

R2 represents OR3, where R3 is hydrogen, alkyl, aryl or ara or R2 represents an aromatic heterocyclic group or -NR'R'. where R4 and R5 are each independently hydrogen, alkyl or alkyl. represents kylcarbonyl, or R4 and R5 represent the nitrogen to which they are attached. Together with the elementary atoms, they form a heterocycle, provided that Y, defined below, forms a bond. Only when represented, R2 represents an aromatic heterocyclic group.

X represents NR, where R is a hydrogen atom, an alkyl group, anru group, an aryl an aralkyl group in which the group is substituted or unsubstituted, or a substituted or unsubstituted aryl group; Represents a group.

Y represents C=O or C=S or a bond, provided that R1 is the aromatic hetero Only when representing a ring group, Y represents a bond.

n represents an integer in the range of 2 to 6] or its tautomeric form, and/or its pharmaceutically acceptable form. and/or pharmaceutically acceptable solvates thereof. Ru.

Suitable aromatic heterocyclic groups include in each ring selected from oxygen, sulfur or nitrogen. Substituted or unsubstituted monocyclic or fused ring heteroaromatics of up to 4 heteroatoms Examples include ring groups.

Preferred heteroaromatic groups have 5 to 7 ring atoms, preferably 5 or Substituted or unsubstituted monocyclic aromatic heterocyclic groups having 6 ring atoms are mentioned.

In particular, the aromatic heterocyclic group is 1, 2 or 2 selected from oxygen, sulfur or nitrogen. Consists of 3, especially 1 or 2 heteroatoms.

When AI represents a 5-membered aromatic heterocyclic group, suitable groups for AI include thiazolyl and oxasilyl, especially oxasilyl.

When A1 represents a 6-membered aromatic heterocyclic group, suitable groups for A1 include pyridyl or or pyrimidinyl, especially pyridyl.

Preferably, A1 is of formula (a), (b) or (C): [wherein, R6 and R7 each independently represent hydrogen or a halogen atom, alkyl or represents an alkoxy group or a substituted or non-substituted aryl group, or R When 6 and R7 are each bonded to adjacent carbon atoms, R6 and R7 are Together with the carbon atoms to which they are attached, they form a benzene ring, where R Each carbon atom represented by 6 and R7 together is substituted or unsubstituted, In the group represented by formula (a), XI represents oxygen or sulfur] represents.

Suitably, A1 represents a group represented by formula (a) above.

Suitably, A1 represents a group represented by formula (b) above.

Suitably, AI represents a group represented by formula (C) above.

A specific form of group (c) is the formula (Co) [In the formula, R6 and R7 are the same groups as defined in formula (C)] It is.

In one preferred embodiment, R6 and R7, taken together, represent formula (d). [In the formula, R8'' and Ra& are each independently hydrogen, halogen, substituted or represents an unsubstituted alkyl or alkoxy group.

Preferably, R8° and R@b each independently represent hydrogen, halogen, alkyl or represents alcoquino. Preferably R1- represents hydrogen. Preferably, R ” represents hydrogen. Preferably, R@° and RO both represent hydrogen.

In a further preferred embodiment, R6 and R7 are each independently hydrogen, alkyl or a substituted or unsubstituted phenyl group, more preferably R6 and R Each 7 independently represents hydrogen, alkyl or phenyl.

Preferably, for the group represented by formula (a), R@ and R7 are - together , represents a group represented by formula (d).

Preferably, for the group represented by formula (b), (C) or (Co), R@ and and R7 both represent hydrogen.

Optional substituents for A2 include halogen, substituted or unsubstituted alkyl and selected from the group consisting of alkoxy.

Preferably, A2 has the formula (e): [In the formula, R10 and R each independently represent hydrogen, halogen, substituted or represents a group represented by [representing unsubstituted alkyl or alkokene].

Preferably RIO and R are each independently hydrogen, halogen, alkyl or or alkoxy.

When RIO or R eyes represents alkoxy, suitable alkoxy groups are methoxy groups It is.

Preferably R'' and R11 each represent hydrogen.

Preferably, A' is a group t4 of the formula -(CHz), -CH(OR')-"c" t.

Preferably A3 represents a group of the formula -CH=C(OR')-.

When R' represents alkyl, suitable alkyl groups are Cl-4 alkyl groups, e.g. , methyl, ethyl, propyl such as n-propyl and 1so-propyl, and and t-butyl. A preferred alkyl group is an ethyl group.

When R1 represents substituted alkyl, specific substituents for the alkyl group include: halo, hydroxy, alkoxy or the group -NR'R' (where R' and R ' each independently represent hydrogen or alkyl, or R" and R ' together with the nitrogen atom to which they are bonded form a 5- or 6-membered heterocycle or the formula -COX2 (where X2 is OH, alkoxy or represents a group represented by the formula -NR'R').

Suitable haloalkyl groups include fluoroalkyl groups such as trifluoroethyl group. Examples include groups.

Generally, when R1 is a substituted alkyl, the substituent is a terminal carbon atom of the alkyl group. attached to the child.

When R1 represents alkylcarbonyl, suitable alkylcarbonyl groups include: Examples include c+-g alkylcarbonyl groups.

When R1 represents aryl, suitable aryl groups include phenyl or naphthyl. Examples include ru groups.

When R1 represents aralkyl, suitable aralkyl groups include benzyl and fluorine. Examples include phenylalkyl groups such as phenylethyl.

A preferred aralkyl group is a benzyl group.

Preferred substituents for any aryl group represented by R1 include: Examples of such substituents include halo, alkyl and alkokyne groups; Rolo, methyl and metquin groups may be mentioned.

Preferably, R-plate is substituted or unsubstituted alkyl or substituted or unsubstituted aralyl. Represents Lukiru.

Preferably R1 is unsubstituted alkyl or unsubstituted aralkyl.

Preferably R2 represents OR3.

Suitably R3 represents hydrogen or alkyl.

When R3 is alkyl, examples of R3 include methyl and ethyl. Ru.

When R2 is a heteroaromatic group, it preferably has 5 ring atoms. llE! The ring atoms are nitrogen and optionally 1.2 or more. or 3 further heteroatoms, e.g. 1,2,4-triazole, 1゜2.4-oxadiazole and tetrazolyl, generally aromatic The aromatic heterocyclic group is C-bonded.

Suitable substituents for aromatic heterocyclic groups include alkyl, aryl, alkoxy and halo, and examples of such substituents include methyl.

When -NR'R5 or -NR'R' represents a heterocycle, preferred heterocycles include each ring. , consisting of 5.6 or 7 ring atoms, optionally ○, S or N. saturated or optionally consisting of one or two further heteroatoms selected from is an unsaturated fused ring or monocyclic heterocycle. Preferred rings are saturated rings. Like The new ring is a monocyclic ring. Preferred further heteroatoms are N or 0. mosquito Examples of such heterocycles include N-pyrrolidinyl, N-piperidinyl and N-mol. Folinil is mentioned.

Further examples of NR'R' include NH.

Preferably R2 represents NR4R3.

Preferably R2 is OR3.

Preferably, R2 represents "OR", where R3 is hydrogen, alkyl, aryl or represents aralkyl, or when R2 represents -NR'R5, Y is CO or C8, preferably Y is CO.

When R2 is an aromatic heterocyclic group, Y is a bond.

Suitably R represents hydrogen or alkyl.

When R is acyl, suitable acyl groups include alkyl groups such as acetyl. Bonyl group is mentioned.

Preferably m represents 1 or 2.

Preferably, m is 1.

Preferably, n is 2.

As mentioned above, the compound represented by formula (1) and its pharmaceutically acceptable salts are: It exists in one of several tautomeric forms, all of which have individual tautomeric forms. Variant forms or mixtures thereof are encompassed by the invention. Expressed by formula (1) The compounds contain at least one chiral carbon and therefore they have one type of chiral carbon. It exists in more than one stereoisomeric form. For example, A3 has the formula -(CH2), -CH(OR +)-, the CH(OR')- carbon atom is a chiral carbon. Ru. Furthermore, A3 represents a group represented by the formula -(CHi)-+CH=C(○R-). In this case, the compound represented by formula (1) exists as a geometric isomer. The present invention whether as individual isomers or as mixtures of isomers, including racemates. All isomeric forms of the compound represented by formula (1) and their pharmaceutically acceptable This includes salts that are

Suitable substituents for any heterocyclic group include alkyl, alkoxy, up to four substituents selected from the group consisting of aryl and halogen; or, alternatively, two substituents on adjacent carbon atoms are Together with the atoms they may form an aryl group, preferably a phenylene group. , the carbon atoms of the aryl group represented by these two substituents are themselves substituted It may be regulated or non-transformable.

As used herein, unless otherwise specified, the term "aryl" refers to phenyl and naphthyl, and the aryl groups described herein include, optionally, halo Gen, alkyl, phenyl, alkoxy, haloalkyl, hydroxy, amino, Nitro, Calhoki/, Alcoquine carbonyl, Alcoquinecarbonyl alkyl, Up to 5 selected from alkylcarbonyloxy or alkylcarbonyl groups , preferably with up to 3 groups.

As used herein, the term "halogen" includes fluorine, chlorine, bromine and It means iodine, preferably chlorine.

As used herein, an alkyl group, whether alone, alkoxy or Containing up to 12 carbon atoms, whether as part of another group such as an aralkyl group It is an alkyl group having a straight or branched carbon chain. Therefore, suitable Examples of alkyl groups include Cl-12 alkyl groups, especially Cl-6 alkyl groups, such as Methyl, ethyl, n-propyl, 1so-propyl, n-butyl, isobutyl or a tert-butyl group.

Suitable substituents for any alkyl group include the term "aryl". and the same substituents as mentioned above.

Preferred aralkyl groups are optionally aryl or as defined herein. or a phenylalkyl group whose alkyl moiety may be substituted.

Suitable acyl groups include alkylcarbonyl groups.

Suitable pharmaceutically acceptable salts include carboxy group salts and acid addition salts. It will be done.

Suitable pharmaceutically acceptable salts of carboxyne groups include, for example, aluminum and the like. Any metal salts, alkali metal salts such as lithium, sodium or potassium, calcium alkaline earth metal salts such as sium or magnesium and ammonium or Substituted ammonium salts, e.g. lower alkyl amines such as triethylamine, 2 -hydroxyethylamine, bis-(2-hydroxyethyl)-amine or Hydroxyalkylamines, such as tri(2-hydroxyethyl)-amine, salts with nocroalkylamines such as cyclohexylamine, or N, dibenzylpiperidine, N-benzyl-β-phenethylamine, dehydroa Biethylamine, N,N'-bisdehydroabiethylamine, glucamine, N- Methylglucamine or pyridine, collidine, quinine or quinoline. Examples include salts with lysine-type bases.

Suitable acid addition salts include sulfates, nitrates, phosphates, borates, hydrochlorides and pharmaceutically acceptable inorganic acid salts such as hydrobromide, as well as acetate, tartrate, maleate, citrate, succinate, benzoate, ascorbate, meth Pharmaceuticals such as sulfonates, α-ketoglutarate and α-glycerophosphate and organic acid addition salts that are legally acceptable.

Suitable pharmaceutically acceptable solvates include hydrates.

Salts and/or solvates of the compound represented by formula (1) can be prepared by conventional means. For example, the sodium salt is prepared and isolated by Prepared by using methoxide.

In a further aspect, the invention provides formula (II): R'-A2-A3'-Y, R2 ゛　(I　I) [where A2 and Y are the same as defined in formula (1) A3 represents a group represented by the formula -(CHJ-CH(OR")-, where Rlo represents R1 or its protected form defined in formula (1), and m is defined in formula (1). A! is the formula −(CHz)−+−CH=C( represents a group represented by OR'°)-, where Rlo is the same as defined above: Rz' represents R2 defined in formula (1) or its protected form, and R'' represents the formula (f)・ A'-X-(CHi)*-0-(f) (wherein A1, X and n are the same as defined in formula (1)) [is a group that can be converted into] A compound represented by is reacted with a suitable reagent capable of converting R8 to group (f). and then, optionally, the following optional step (i): a compound represented by formula (1) a step of converting into another compound represented by formula (I), (11) removing any necessary protecting groups, and (iii) in formula (1) A pharmaceutically acceptable salt of the indicated compound and/or a pharmaceutically acceptable salt thereof Formula (I), characterized in that one or more of the steps for preparing a solvate are carried out. or its tautomeric form, and/or its pharmaceutically acceptable form. Provided is a method for producing a salt thereof and/or a pharmaceutically acceptable hydrate thereof. There are also things.

Suitably R" represents HX (CH2), O-, where X and n are of the formula As defined in (I) or R8 represents OH.

Preferably R" represents OH.

When Ro is HX (CHz)-0-, it has the ability to convert Ro to group (f) A suitable reagent has the formula (II1) A'-R' (I I I) [wherein A1 is the same as defined in formula (1), and Rlo is a leaving group ] It is a compound shown by.

Suitable leaving groups R' include halogen atoms, preferably chlorine or bromine atoms. , or a thioalkyl group, such as a thiomethyl group.

Generally, Rlo is R1. Preferably, R1′ represents OR3°; Here, R3' represents hydrogen, alkyl, aryl, aralkyl, or R2' represents -NR'R' as defined above.

When Ro is OH, a suitable reagent has the formula (IIIA): AI-X-(CH2) , -OR' (I I IA) [where A1, X and n are in formula (1) As defined, Ro represents a leaving group such as a tosylate or menlate group ] It is a compound shown by.

The reaction between a compound of formula (II) and a suitable reagent is carried out under conditions appropriate to the particular compound indicated and the reagent selected: e.g. ,R.

Compounds represented by formula (II) where represents HX (CH2), O-, and compounds represented by formula (I) The reaction between the compounds of II) can be carried out in a suitable solvent, such as dimethylform. mamide at a temperature that provides a suitable rate of formation of the compound of formula (I), e.g. For example, at elevated temperatures in the range of 50°C to 120°C, preferably with a salt such as triethylamine. carried out in the presence of groups.

In further examples, compounds of formula (II), wherein R8 is OH; and The reaction between the reagents represented by the above formula (IIIA) can be carried out using dimethylformamide, etc. In an aprotic solvent at low to high temperatures, e.g. For example, at 80° C., preferably in the presence of a base such as sodium hydride.

In another embodiment, R1 in the compound represented by formula (IIIA) represents H, and the formula ( When R" in the compound represented by I) is OH, a suitable reagent is die Provided by tylazodicarpokylate and triphenylphosphine: The coupling reaction is carried out in a suitable solvent at low to moderate temperatures, e.g., tetrahydrofuran. medium, at temperatures ranging between 0 and 60°C.

Formula (1■) in which A3° represents a group represented by the formula -(CH2), -CH(OR1°)- The compound represented by formula (IV) R'' A2 (CH2)-CY R' (IV) [wherein A2, Y and m are The definition is the same as in the compound represented by formula (1), and R1 is a group R° or a group is a group convertible to R°, and R9 is R2' or a protecting group as defined above] A carbene source represented by formula (V).

R1’○H (V) A compound represented by [wherein R1' is the same as defined in formula (II)] Then, if desired, the group R1 is converted into the group R°, and any protecting group It is also produced by removing.

Preferably Y is CO. Preferably, Re is OR1' or -NR' It is Rs.

A preferred carbene source of formula (IV) is a carbene source of formula (IVA) [wherein A2, R' , R', Y and m are the same as defined in formula (IV)] By reacting a substance with a rhodium (II) salt such as rhodium acetate (TI) Therefore, it is obtained.

The conditions used when producing the carbene represented by formula (IV) from (IVA) are: Of course it depends on the particular carbene chosen, but in general usage e.g. For example, when (IV) is a carbene and (IVA) is a carbene source, a suitable The conditions are Tetrahedron Lett, The conditions are similar to those disclosed in No. 1973.2233.

The reaction between the carbene of formula (IV) and the compound of formula (V) is under customary conditions, generally in an inert solvent such as benzene, or where practicable. in compound (V) as a solvent at a temperature that gives a favorable rate of formation of the desired product. , generally carried out at elevated temperatures, for example at the reflux temperature of the solvent. Preferably used The conditions are those disclosed in Tetrahedron Letters, 1973.2233. The same conditions apply.

When the carbene source is a compound represented by formula (IVA), The compound has the formula (Vl): R’-A”=(CH2)-CHY R’(VI)■ N.H.

[wherein A'', R', R', Y and m are in the compound represented by formula (IV) This is the same definition as The compound represented by is diazotized with a suitable diazotizing agent, and then, if desired, the group R It is produced by converting ゝ into a group R'' and removing any protecting groups.

Suitable diazotizing agents are alkyl nitrites such as 1so-amyl nitrite.

Suitable diazotization conditions for producing the compound represented by formula (IVA) include, for example: , Tetrahedron Letters, 1971.4495, etc. This is a customary condition.

The group R'' is converted to the group R° by suitable conventional means. For example, if R1 is -OH and Ro represents HX-(CH2)-0-, then a suitable conversion is when R1 is O A compound represented by the formula (Vl) which is H is represented by the formula (g).R'-X-(CHz), -O H (g) [In the formula, X and n are the same as defined in formula (1), and R'' is a protecting group. A certain child Coupling with a compound represented by This is done by removing.

Said last reaction is generally carried out in the presence of a suitable coupling agent. suitable Coupling agents include diethyl azodicarboxylate and triphenylphosph It is in. The coupling reaction is carried out in a suitable solvent at low to moderate temperatures, e.g. It is carried out in lahydrofuran at temperatures ranging from 0 to 60°C.

Generally, a compound of formula (IV) in which Ro is OH, Rh in (IV) is OH or protected OH , for example bennylated OH.

The compounds of formula (V) are known commercially available compounds, or they are , manufactured using methods similar to those used to manufacture such compounds. It will be done.

The compound represented by formula (Vl) is a known compound, or they are known Methods similar to those used to produce compounds, e.g., tetrahedron - Manufactured using the method disclosed in Letters, 1971.4495, with special , R9 is 0CHI, m is 1, A2 is 1,4-phinidine, Compounds where R1 is OH are commercially available compounds.

The compounds represented by formula (g) are known compounds, or they are known compounds. Methods similar to those used to prepare the compounds, e.g. EPO 35621 manufactured using the method disclosed in 4.

represented by the formula (1) in which A represents a group represented by the formula -(CH2), -CH(OR+)-; or its tautomeric form, and/or its pharmaceutically acceptable The salt and/or its pharmaceutically acceptable solvate has the formula (Vll)+A' X (CH2)-OA" (CH2), -CH-Y-R' (VI I) OH [In the formula, A1, A2, XSY, m and n are the same as defined in formula (II) and R9 is the same as defined in formula (IV)] The gender form is the formula (Vllll) R1-L' (VI I I) [In the formula, R1 is the same as defined in formula (1), and Ll is a leaving group or an atom. Represents a child] React with the compound represented by, and then, if desired, any of the following steps.

(i) Converting the compound represented by formula (1) to another compound represented by formula (T) process, (11) a step of removing any protecting groups, and (iii) a step represented by formula (1); a pharmaceutically acceptable salt of the compound and/or a pharmaceutically acceptable solvate thereof; It can also be manufactured by performing one or more of the steps of manufacturing a product.

Suitably Ll is a halogen atom, for example a bromine atom.

Suitable active forms of the compound of formula (Vll) include anionic forms such as salt forms and Especially in the alkali metal salt form, for example the sodium salt.

Active forms of compounds of formula (VII) are prepared by appropriate conventional methods. .

For example, the anionic form of the compound represented by formula (Vll) is represented by formula (Vll). treatment of the compound with a base, such as a metal hydride base such as sodium hydride. Manufactured by

The reaction conditions for the reaction between the compounds of formula (Vll) and (VITI) are , generally conventional alkylation conditions. For example, a compound represented by formula (Vll) The reaction between the salt form of the compound and the compound represented by the formula (Vlll) is carried out using dimethylforma in an aprotic solvent such as amide, at a temperature that provides a suitable rate of formation of the desired product; Generally, it is carried out at an elevated temperature, such as in the range of 40<0>C to 100<0>C, for example 80<0>C.

Preferably, the formation of the active form of (VII) from (VII), e.g. Formation of the salt form refers to the formation of a salt form of the active form of (VII) of formula (VIII) as defined above. It is carried out in 1 n-sit υ before the reaction with the compound.

The compound represented by formula (VII) has formula (IX): R' A" (CHz)-CH Y-R’(IX)T [In the formula, R'', R9, A2, Y and m are the same as defined above, and T is hydrogen or a hydroxyl protecting group] A suitable reagent capable of converting Ro to the formula (f) defined above Manufactured by reacting with drugs.

A reagent capable of converting R" into a group represented by formula (f) is represented by formula (1) Same as the above definition regarding the formation of the compound from the compound of formula (II) be.

Suitable definitions for Ro include those listed above.

Suitable reaction conditions for the reaction of compounds of formula (IX) and appropriate reagents As described above for the preparation of compound (II) using this appropriate reagent. can be mentioned.

Preferably, in the compound represented by formula (IX), R1 represents a hydroxyl group. A particularly suitable reagent is a compound of formula (IIIA) as defined above.

A compound represented by the formula (IX) in which Ro is a hydroxyl group and a compound represented by the above-defined formula ( The reaction between the reagents shown in IIIA) can be performed using aprotons such as dimethylformamide in a neutral solvent at a low temperature to a high temperature, for example, in the range of 50 °C to 120 °C, for example, 80 °C, Preferably, it is carried out in the presence of a base such as sodium hydride.

The compound represented by formula (IX) in which R1 is OH is a known compound or are prepared by methods similar to those used to produce known compounds, e.g. , Dictionary of Organic Compounders of Organic Compounds), 5th edition, Volume 3, No. 3222 Page, Chapman & Hall, or D.H. Williams (D, H.

William+*s) et al., Journal of the Chemical Society (J,C Het Soc, Section 8, 1969.439, or Jay March (J. , March), Advanced Organic Chemistry (Advance) ed Organic Che+*1stry), 3rd edition (1985), Willi Disclosed to Wiley I interscience or, for example, as disclosed in International Application Publication No. WO92102520. Compounds prepared by the method shown.

AJ is represented by the formula (1), which is a group represented by the formula -(CHz)-CH (○R Lee) a compound, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof; and/or a pharmaceutically acceptable solvate thereof has the formula (X): A' Hz)-OA"-(CHz)-CY-R' (X) [wherein A1, A2, X, Y Sm and n are the same as defined in formula (I), and R is as defined in formula (IV). The carbene source represented by the formula (V) of the above definition is react with the compound and then optionally any of the following steps.

(i) Converting the compound represented by formula (1) to another compound represented by formula (1) process, (11) a step of removing any protecting groups, and (iii) a step represented by formula (1); a pharmaceutically acceptable salt of the compound and/or a pharmaceutically acceptable solvate thereof; It can also be manufactured by performing one or more of the steps of manufacturing a product.

A suitable carbene source represented by formula (X) is represented by formula (X　I　　):N! In formula c, A'SA'', R9, X, Y, m and n are the same as defined in formula (X). It is the same] Reacting the compound represented by with rhodium (II) salt such as rhodium (II) acetate obtained by letting

The carbene represented by the formula (X) is the carbene represented by the formula (IV), the carbene represented by the formula (IVA ) using methods similar to those used for production from compounds shown in It is prepared from a compound of formula (XI) by:

The reaction conditions for the reaction between the compounds of formula (X) and (V) are as follows: ) and (V) are equivalent to the conditions used in the reaction between the compounds represented by .

The compound represented by the formula (XI) is a compound represented by the formula (I) or the compound represented by the formula (1). and (IIrA) The method is used to obtain compounds of formula (IIIA) and (VI) by reaction between and then as described above for the conversion of formula (Vl) to (IVA). Diazotize sea urchin.

A3 has the formula -(CH2), -CH=C(OR or -(CH, -CH(O A compound represented by formula (1) representing a group represented by R')-, or a tautomer thereof form, and/or its pharmaceutically acceptable salts, and/or its pharmaceutically acceptable salts. The accepted solvate has the formula (Xll) AI-X-(CHI), -0-A”-(CHI), 1-CHO(X11) [in the formula , AI, A2, X, m and n are the same as defined in formula (1)] from the CHO carbon atom to the above-defined 2CH=C(OR')-Y, R'' is reacted with a reagent capable of converting into the group represented by, and then, if desired, the group -C By reducing H=C(OR+)-, As is represented by the formula -(CHt)--CHOR'- A compound representing a group is obtained, and then, optionally, any of the following steps: (i) Formula A step of converting the compound represented by (1) into another compound represented by formula (■), (11) a step of removing any protecting groups, and (iii) a step represented by formula (1); a pharmaceutically acceptable salt of the compound and/or a pharmaceutically acceptable solvate thereof; It can also be manufactured by performing one or more of the steps of manufacturing a product.

From the CHO carbon atom to a group represented by the above-defined formula -CH=C(OR+)-Y, R'' Suitable reagents capable of converting into are Wittig reagent or preferably the formula (X IIT): In formula c, R1', Rz' and Y are the same as defined in formula (II), and R l　O represents a C+-S alkyl group, preferably a methyl or ethyl group] The Wadsworth-Emmons reagent shown.

The reaction between the compounds represented by formulas (Xll) and (Xlll) can be carried out using the conventional Wadswer method. Emmons reaction conditions, e.g. aprotic solvents such as tetrahydrofuran at moderate to low temperatures to room temperature, for example in the range 08 to 25°C, conveniently at room temperature, preferably Alternatively, it is carried out under an inert atmosphere and under anhydrous conditions. Preferably, formula (XII The compound represented by I) is preferably added before the addition of the compound represented by formula (Xll). , for example by addition of a base such as sodium hydride or n-butyllithium. , a compound in which activated A3 represents a group represented by the formula -(CH, , CH(OR) 13 to obtain is a group represented by the formula (CH2)-+CH=C(OR')- Reduction of a compound representing, for example, 10% in an alkanol solvent such as ethanol Using conventional reduction methods such as catalytic reduction using palladium-charcoal catalysts, certain Yes, Tetrahedron Letters (Tet, Lett), 1986.27 ．． Magnesium metal/metal/solvent systems such as methanol disclosed in 2409 This is done through the use of.

The compound represented by formula (Xll) converts an ester group into a carbonyl group. Formula (XIIA): A'X (CHz)-OA" (CH z)--+-COzR' (XIIA) [wherein A1, A2, X, m and n is the same as the definition in formula (1), and R.

is hydrogen or a C1-6 alkyl group, preferably a methyl group; a convenient method is, for example, by hydrogenation in tetrahydrofuran. The ester group is reduced using a metal hydride reducing agent such as lithium aluminum. , to obtain the primary alcohol, then pyridine-trioxide in dimethyl sulfoxide By the use of oxidizing agents such as sulfur complexes, the primary alcohol is oxidized to the desired including obtaining a carbonyl group of.

The compound represented by formula (XIIA) is represented by formula (IIIA) defined above. Using a compound, formula (X I I B) HO-A2-(CH2), -1-CO2R' (XI IB) [wherein A2, m and Ro are the same as defined in formula (XIIA)] Manufactured from

Preferably, a reaction between compounds represented by formula (IIIA) and (XIIB) The reaction conditions for the reaction between the compounds represented by formulas (II) and (IIIA) are The reaction conditions are as described above for the reaction.

A3° represents the formula -CH=C(ORji)- or -CHtCH(OR1°)- The compound represented by formula (II), or its tautomeric form, and/or its Pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof have the formula (X　I　V)R’-A4-CHO(X　I　V) [wherein R5 and A2 are the same as defined in formula (IV)] The compound is converted from the CHO carbon atom to the formula -CH=C(OR")-YRz' as defined above. reaction with a reagent capable of converting the group shown, then optionally converting the group -CH =C(OR1°)- is reduced to obtain a group represented by the formula -CHx-CHOR"-, It is then produced by removing the protecting group, if desired.

Preferably R1 is a protected OH group.

Compound (XIV) (DCHO carbon atom defined above) Formula -CH=CH(OR") -Y.

A suitable reagent having the ability to convert into the group represented by R2° is represented by formula (II) as desired as defined by the nature of RP and R2' in the desired compound. A compound represented by the above-defined formula (Xlll) in an optionally more protected form be.

Suitable conditions for the reaction between the compound of formula (XIV) and the reagent The above conditions for the reaction between compounds of formulas (Xll) and (Xll) Same as the case.

The compound represented by formula (X11), especially the compound where m is 1, is a compound represented by EPO3062 It is manufactured by the method disclosed in No. 28.

The compound represented by formula (XIIB) is a known commercially available compound, or They are manufactured by similar methods used to manufacture such compounds. or they can be used, for example, to convert commercially available carboxylic acids into alkyl esters. prepared from such compounds by.

The compounds represented by 2〇NII) are known compounds, or they are Methods similar to those used to produce known compounds, e.g. ・Dell Chemie (Annalen Chemie) 1966.699.53 or Journal of Organic Chemistry (J, Org, Chem , ) Compounds produced by the method disclosed in 1983.48.3408 It is a thing.

The compounds represented by formula (XIV) are known compounds, or they are Methods similar to those used for producing known compounds, e.g. EP 03 06228.

A3 represents a group represented by the formula -C1h-CH(OR')-, and R1 represents an alkyl group; The compound represented by formula (1), or its tautomeric form, and/or its pharmaceutical Pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof have the formula ( XV): Al-X-(CHI), -0-A"-CH2-CH(OR')-CN (XV) [wherein AI, AI, R1, X and n are as defined in formula (1) The same is the same] is hydrolyzed to form a compound represented by formula (1) in which R2 is OH. and then optionally converting R2 as OH to another R2. , then, if desired, perform any of the following steps: (1) Converting the compound represented by formula (1) to another compound represented by formula (1) process, (ii) a step of removing any protecting groups, and (iii) a step represented by formula (1) A pharmaceutically acceptable salt of the compound and/or a pharmaceutically acceptable solvent thereof It can also be produced by performing one or more of the steps for producing a compound.

Hydrolysis of the compound of formula (XV) can be carried out using the customary conditions for nitrile hydrolysis. and reagents, e.g. 10% sodium hydroxide in methanol. Basic hydrolysis is used.

Conversion of R2 as OH to another R2 can be accomplished by any method such as the methods described below. It may also be done by using any convenient method.

The compound represented by formula (XV) can be prepared by reaction with trimethylsilyl cyanide, Formula (XVI): A’ X (CHi)-OA” CHz CH (OR”) OR” (XVI) In the formula, AI, 6. ! , X and n are the same as defined in formula (1), and R 1"=R1" and represents alkyl] Manufactured from the compound shown in

The reaction between the compound represented by formula (XVI) and trimethylsilyl cyanide is in an inert solvent such as chloromethane at low to room temperature, conveniently at room temperature. It is often carried out in the presence of a Lewis acid catalyst such as a boron trifluoride-ether complex compound. It will be done.

The compound represented by the formula (XVI) is a compound represented by the formula (XVIII): R1-OH(XVI 1) Reacting with a compound represented by [wherein R1" is the same as defined above] According to the formula (XVrI): A' X (CHz)-0A2-CH=CHOR' “(XVII) [where AI, AI, Rlo, X and n are in formula (XV)] It is manufactured from the compound shown in

The reaction between the compounds of formulas (XVII) and (XVIII) is preferably carried out by Using a compound of formula (XVIll) as a solvent, generally refluxing the solvent I) Preferably carried out in the presence of toluenesulfonic acid at elevated temperatures such as .

Preferably Rlo is methyl.

The compound represented by formula (XVII) is a compound represented by formula (Xll) as defined above, where m is 1. from the CHO carbon atom represented by the formula (X11) of the compound represented by the above-defined formula -C Produced by reaction with a reagent capable of converting into a group represented by H=CH-0R+ It will be done.

The reagent preferably has the formula (XIX): [Ph5PCH2-ORII''C f-(XIX) [wherein R1 is the same as the definition in formula (1)] This is a very strong reagent.

The reaction between the compounds represented by formulas (X11) and (XIX) can be carried out using the conventional Uinoti method. reaction conditions, e.g. in an aprotic solvent such as tetrahydrofuran, at low temperature. ~ in chamber 1, for example in the range -10° to 25°C, conveniently at room temperature, preferably is carried out under an inert atmosphere under anhydrous conditions. Preferably, represented by formula (XIX) For example, the compound represented by formula (Xll) may be added with sodium hydride. of bases such as lithium, n-butyllithium or lithium neuisopropylamide. It is suitably activated by addition.

Compounds represented by formulas (XVIll) and (XIX) can be prepared from known compounds. methods similar to those used to create March), Advanced Organic Chemistry (Advanced) Organic Chemistry), 3rd edition (1985), Willi 4-I Disclosed in Wiley Interscience It is a compound produced by a method.

AI is (CH2), -CH(OR+)-, and R1 is a C-bonded aromatic heterocycle a compound of formula (I), or its tautomeric form, and/or The pharmaceutically acceptable salt and/or the pharmaceutically acceptable hydrate thereof may be The compound represented by the formula (Xll) defined above can be converted into a compound represented by the formula (XX) [wherein het-CH is , an aromatic heterocycle containing at least one carbon atom, represented by R2 is the basis] and then the compound in which R1 is hydrogen is reacted with the active form of the compound represented by R1 is converted into the compound represented by formula (1), and then, if desired, (i) the compound represented by formula (1) (11) any necessary protection. (iii) A pharmaceutically acceptable salt or a compound of formula (1) is removed. and/or a pharmaceutically acceptable solvate thereof. Ru.

A preferred active form of the compound of formula (XX) is a salt form, such as a lithium salt form. .

The active form of the compound represented by formula (XX) is Adv, Heterocyclic known methods such as those disclosed in Chew, 1993.56.155 In an aprotic solvent such as tetrahydrofuran, the aromatic heterocyclic group H et-CH or Het-CL (where L is a leaving group such as halogen) with a suitable conventional activator, such as a salt former such as an alkyl lithium. Manufactured by

A3 is (CH2)-CH(OR')-, and R2 is a C-bonded tetrazolyl group A compound represented by a certain formula (+), or its tautomeric form, and/or its Pharmaceutically acceptable salts and/or pharmaceutically acceptable hydrates thereof have the formula ( XXI):OR' C.N. [In the formula, A1, A! , R1, X, m and n are the same as defined in formula (1). Preferably, a compound represented by C is treated with an azide ion source such as an azide salt. Produced by reaction in an alkali metal azide such as sodium azide. will be built.

The compound represented by formula (XXI) can be prepared, for example, by using POCIg, in which A3 is (C H2), -CH(OR'), formula (1) t' where $+S,YR'' is C0NHz Prepared by dehydrating the indicated compound.

The reaction between the compound of formula (XXI) and the azide ion source can be carried out under conventional conditions. It takes place below. For example, if sodium azide is the azide ion source, the reaction The reaction is generally carried out at elevated temperature in an aprotic solvent such as dimethylformamide. For example, at the reflux temperature of the solvent, preferably in the presence of trimethylsilyl chloride. It will be done.

As said conversion of a compound represented by formula (1) to another compound represented by formula (1) a) converting a group R into another group R; b) converting a group OR+ into another group OR+ c) converting a group Y, R2 in which Y is CO into another Y, R1; d) converting the group CO,R'' into another group C3,R'' and e) the group -CH= Examples include reducing C(OR+)- to the group -CH2-CH(OR-).

Said transformation is optionally to any of the intermediate compounds described herein. It will be done.

Conversion of a compound represented by formula (1) to another compound represented by formula (1) This may also be done by using any suitable conventional means.

A preferred conversion from a group R to another group R is the conversion of a group R representing hydrogen into a group R representing an anlu group. such conversion using appropriate conventional acylation methods. , for example, treating a suitably protected compound of formula (I) with an acylating agent. It is done by Therefore, acetic anhydride has the formula (I) where R is acetyl It is used to produce the compound shown in

A preferred conversion of a group OR+ to another group OR+ is when R] represents substituted alkyl. , conversion of one substituent to another, e.g. to obtain a CH20H substituent. , including the reduction of the C02R'' substituent where R'' is CI-@alkyl.

The reduction is carried out using conventional reduction methods, e.g. in a solvent such as methanol. This is done using a borohydride reducing agent such as sodium borohydride.

Suitable conversions from the group YR1 in which Y is CO to another group Y, R1 include (i) R "Group Y, OR" is alkyl, aryl or aralkyl, Y is CO Hydrolyzing to group Y, ○H, (ii) R” cuff/L, coxyteal group Y, R” is diaminated with a CO7’J group Y, NR4R’i, (iii) The group Y and OH defined above are halogenated to form the corresponding acid halide and then amination of the halide to form the group Y, NR where Y is co 'R' as ll: and (iv) The group YOH is esterified to form a group Y-0 alkyl or obtaining a Y-0 aralkyl, and (v) Group Y, NH2 where Y is CO, Y is a bond, and C-Het is a C-bond. An example is conversion to a group Y-C-Het, which is an aromatic heterocyclic group.

A suitable hydrolysis method useful in transformation c(1) is, for example, in aqueous methanol. A conventional ester hydrolysis method using alkali hydroxides.

Preferred amination methods for transformation c(ii) or c(iii) include: For example, treatment with aqueous ammonia in tetrahydrofuran/methanol Examples of commonly used methods include:

Suitable halogenation methods for conversion c(iii) include, for example, oxychloride Conventional methods such as treatment with Salil may be mentioned.

The preferred esterification method for transformation c(iv) is the conventional method, but Therefore, the alkyl ester can be extracted with a suitable alkanol such as methanol in the presence of an acid. Aralkyl esters are produced by using sodium salts such as Salt-formed YOH with a suitable aralkyl halide such as benzyl bromide Manufactured by processing.

From the group Y, NH, where Y is CO, Y is a bond and C-Het is a C-bonded aromatic Preferred conversions to the group Y-C-Het, which is a group heterocyclic group, include a) 1.2.4 -) hydrazine, e.g. hydrazine hydrate and reaction with amide acetals such as dimethylformamide dimethyl acetal, or b) Hydroxylamine, e.g. to obtain 1.2.4-oxadiazole For example, hydroxylamine hydrochloride, and dimethylformamide dimethyl acetate Reaction with amide acetals such as can be mentioned.

Suitable transformations of the group CO, R1 to another group CS, R'' can be carried out using conventional methods. , for example, at a temperature that provides an acceptable rate of formation of the desired product. by using Lawesson's reagent in a solvent such as toluene at the reflux temperature of the solvent. will be carried out.

A suitable reduction of the group -CH=C(OR-) to the group -CH2CH(OR+)- is described above. carried out using conventional reduction methods such as the catalytic reduction or gold I/solvent reduction method described above. .

Any of the above reactions including the above transformations (a), (b), (C), (d) and (e) Also, any reactive groups on the substrate molecule can be removed using conventional chemical practices. shall be understood to be protected pursuant to the following.

Suitable protecting groups in any of the above reactions are those commonly used in the art. The protecting group used. Thus, for example, as a suitable hydroxyl protecting group is a benzyl or trialkylsilyl group.

Methods for forming and removing such protecting groups are conventional methods appropriate for the molecule being protected. It is the law. Thus, for example, a benzyloxy group can lead to suitable compounds with benzylbromide. produced by treatment with a benzyl halide such as Zyl, and then the desired By catalytic hydrogenation or moderate ether cleavage such as trimethylnoryl iodide The benzyl group is conveniently removed by using a reagent.

If desired, isomerism of the compound represented by formula (1) and its pharmaceutically acceptable salts Forms are produced as individual isomers using conventional chemical methods.

However, for certain compounds of formula (I), the A novel method for separating optical isomers is provided. In fact, a newly discovered The method is such that the chiral carbon of such a compound is a carboxy ester group and Zl is an alkyl Optics of compounds in which the group OZ'l is dibonded as kyl, aryl or aralkyl It appears that the isomers can be separated.

Therefore, the present invention relates to Rhizopus dele+I Iar), Rhizopus arrhizus, Rhizopus arrhizus Lipase or mucor derived from Rhizopus LIPF4 Using lipase from Mucor m1ehei, one mirror The ester group C02Z of the enantiomer is converted into a carboxyl group enantioselectively (enantioselectively). oselectively) and then optionally enantiomerically enriched to isolate the containing product carboxylic acid or the enantiomerically enriched substrate ester. The formula (H), which consists of OZ■ [In the formula, C8 is a chiral carbon, Z is a Cl-1□alkyl group, and Zl is a Cl-12 alkyl, aryl or arylc+-+i alkyl group ] for separating optical isomers of a compound (substrate ester) consisting of a group represented by The present invention provides a method.

Enantiomerically enriched product carboxylic acid and/or enantiomerically enriched product The substrate ester to be prepared can be prepared by conventional extraction methods such as phase separation and/or extraction into a suitable solvent. and optionally chromatography. good.

In another isolation method, prior to isolation, the enantiomerically enriched substrate ester is converted by hydrolysis to each carboxylic acid and then isolated by conventional methods. Ru. In an advantageous embodiment of the invention, the enantiomerically enriched substrate ester is Hydrolysis by treatment with pase gives the individual carboxylic acids.

In the compound represented by formula (I) falling within the scope of formula (H), Z represents Rj and Zl is These compounds represent R1. Therefore, the new method shows that A3 is (CHz) -CH(OR')-, Y represents CO, R2 is OR3, and Al5A2 , R1, R3, X, m and n are the same as defined in formula (1), A compound enriched in the enantiomer shown (hereinafter referred to as a compound represented by formula (IA)) used to produce

Microbial lipase enzymes are described in the Journal of Bacteriology (J, Bac teriol, ), 1982, Tsuta vol. 150, 498-505, H. Gilba Ruth (H, G11bert) and M. Tully, Europe Patent Application No. 0198440 and UK Patent No. 1.474.519 Obtained by conventional culture techniques as disclosed. The lipase is pure Isolated as an enzyme, or alternatively, a suitable lipase source can be taken inside.

Preferably, the microbial lipase enzyme is a pure or partially pure enzyme preparation. It is commercially available.

Hydrolysis of the compound of formula (H) can be carried out using a suitable aqueous solution with controlled pH. in a medium, for example in an aqueous buffer or by addition of an aqueous sodium hydroxide solution. pH 1 generally gives a suitable rate of formation of the desired product in a pH controlled solvent. Typically, the pH range is from 5 to 9, for example from 6 to 8, for example at pH 7.

The hydrolysis is carried out at a temperature that provides a suitable rate of formation of the desired product, generally from low temperature to Room temperature, e.g. a temperature in the range of 5°C to 40°C, e.g. in the range of 20°C to 40°C, preferably Preferably, it is carried out at a temperature in the range of 20°C to 30°C, for example, 23°C.

Generally, the substrate mixture is acetone, tetrahydrofuran, dimethyl sulfokide , organic solvents that are water-miscible solvents such as dimethylformamide or acetonitrile. It is introduced into the reaction system as a solution in a medium.

The stereoselective method is (-)3-[4-[2-[N-(2-benzoxasilyl) -N-methylamino]ethoxy]phenylco-2-methoxypropanoic acid Compounds with stereochemistry at the carbon atom marked with an asterisk that is identical to the isopolar elementary atom (IA ) is selectively hydrolyzed.

Properties that provide optimal enrichment for compounds (H) that are enriched in a particular enantiomer. Reaction conditions such as specific acidic pH and reaction temperature are determined by routine experimentation. .

Suitably, the stereoselective reaction is such that the desired enantiomer is more than 70% W/W. Alternatively, a compound (I A). Most preferably, the product from the stereoselective method is the desired mirror image. The isomer is 80-100% w/w, preferably 90-100% w/w, e.g. 90-95%, most preferably 95-100%, e.g. 95%, 96%, 9 7%, 98%, 99% or 100% W/W enantiomer-enriched in the form present Compound (IA) is provided.

The enantiomerically enriched compounds (IA) as described above form a further aspect of the invention. It seems that it will. Therefore, the present invention provides enantiomerically enriched compounds (IA ), or tautomeric forms thereof, and/or pharmaceutically acceptable salts thereof; and/or pharmaceutically acceptable solvates thereof.

The present invention provides that the desired isomer contains more than 50% w/w, preferably more than 70% w/w. More preferably, compounds that are enantiomerically enriched present in more than 80% W/W (IA), or its tautomeric form, and/or its pharmaceutically acceptable Also provided are salts and/or pharmaceutically acceptable solvates thereof.

Most preferably, the enantiomerically enriched compound (IA) is 80-100% W /W, preferably 90-100%, e.g. 90-95%, most preferably 95-100%, e.g. 95%, 96%, 97%, 98%, 99% or 10 0% w/w is in the form of the desired isomeric form of the compound of formula (IA) .

In a preferred embodiment, a compound of formula (IA), preferably in optically pure form, compounds, or their tautomeric forms, and/or their pharmaceutically acceptable salts, and/or pharmaceutically acceptable solvates thereof.

The absolute stereochemistry of a compound is determined using conventional methods such as X-ray crystallography. .

As noted above, the compounds of the invention have been shown to have useful therapeutic properties.

Accordingly, the present invention provides compounds of formula (1) useful as active therapeutic substances. , or its tautomeric forms, and/or its pharmaceutically acceptable salts, and/or pharmaceutically acceptable solvates thereof.

Therefore, the present invention provides compounds of formula (I) useful for the treatment and/or prevention of hyperglycemia. or its tautomeric form, and/or its pharmaceutically acceptable form. and/or pharmaceutically acceptable solvates thereof. be.

In a further aspect, the present invention provides compounds useful for the treatment and/or prevention of hyperlipidemia. The compound represented by (1), and/or its tautomeric form, and/or its and/or pharmaceutically acceptable solvates thereof. There is also something to offer.

As mentioned above, the present invention provides treatment for hypertension, cardiovascular disease, and certain eating disorders. A compound of formula (1), or a tautomeric form thereof, useful for therapy, and/or or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable solvent thereof It also provides Japanese food.

Cardiovascular diseases include in particular atherosclerosis.

Some eating disorders, especially those with under-eating, such as anorexia nervosa, disorders related to obesity and anorexic bulimia (anorexic bulimia); For over-eating such as orexia buliaia including regulation of appetite and eating behavior in patients suffering from related disorders .

A compound represented by formula (1), or a tautomeric form thereof, and/or a pharmaceutical thereof Pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof are or, preferably, as a pharmaceutical composition comprising a pharmaceutically acceptable carrier. given.

Therefore, the present invention provides a compound represented by general formula (1) or a tautomer thereof form, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. and a pharmaceutically acceptable carrier thereof. be.

As used herein, the term "pharmaceutically acceptable" refers to human and veterinary including pharmaceutical compounds, compositions and ingredients, such as "pharmaceutically acceptable salts" The term encompasses veterinary acceptable salts.

The composition may be in bag form, optionally accompanied by instructions for use.

Generally, the pharmaceutical compositions of the present invention are suitable for oral administration, but also for injection and transdermal absorption. Compositions for other routes of administration are also envisioned.

Particularly suitable compositions for oral administration are unit dosage forms such as tablets and capsules. It is a state. Other fixed unit dosage forms such as powders present in sachets are also used. .

According to conventional pharmaceutical practice, carriers include diluents, fillers, disintegrants, wetting agents, lubricants, etc. additives, colorants, flavoring agents or other customary auxiliaries.

Typical carriers include, for example, microcrystalline cellulose, starch, starch glycerin, Sodium cholate, polyvinylpyrrolidone, polyvinylpolypyrrolidone, steel Mention may be made of magnesium arylate or sodium lauryl sulfate.

Most preferably, the composition is formulated in unit dosage form. Such a unit dose is Usually 0.1 to 1000 mg, more typically 0.1 to 5001 g, especially 0. Contains amounts of active ingredient ranging from 1 to 25 Qmg.

Additionally, the present invention provides a method for treating and/or preventing hyperglycemic humans or patients in need of treatment and/or prevention. A compound represented by general formula (1) or a tautomeric form thereof, to a non-human mammal, and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable salt thereof. to a human or non-human mammal, characterized in that a non-toxic effective amount of a solvate is administered to a human or non-human mammal. A method for treating and/or preventing hyperglycemia in mammals is provided.

The present invention further provides for the treatment of hyperlipidemic humans or non-human mammals in need of treatment. A compound represented by formula (1), or a tautomeric form thereof, and/or a pharmaceutical thereof non-toxic pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof. Hyperlipidemia in a human or non-human mammal, characterized by administering an effective amount. The present invention provides a treatment method for

Conveniently, the active ingredient is administered as a pharmaceutical composition as defined above, which form a particular aspect of light.

Treatment and/or prevention of hyperglycemia in humans and/or treatment of hyperlipidemia in humans. In therapy and/or prevention, the compound represented by general formula (1) or their mutual variant forms, and/or pharmaceutically acceptable salts thereof, and/or pharmaceutically acceptable salts thereof; The pharmaceutically acceptable solvate, at the dosages indicated above, is effective for a 70 kg adult generally a total daily dose of 0.1 to 6000+g, more typically about 1 to 1500I It is administered in such a way that it ranges from 1 to 6 times a day.

Active in the treatment and/or prevention of hyperglycemia in non-human mammals, especially dogs. The ingredients are usually administered once or twice a day at approximately 0.025 g/kg to 25 m administered orally in an amount ranging from 0.11 g/kg to 2Q mg/kg. It will be done. A similar dosing strategy can be used to treat hyperlipidemia and/or in non-human mammals. is suitable for prevention.

Dosing strategies for the treatment of hypertension, cardiovascular disease, and eating disorders generally include The administration policy is as described above regarding glycemia.

In a further aspect, the invention provides a method for the preparation of a medicament for the treatment and/or prophylaxis of hyperglycemia. The compound represented by formula (1), or its tautomeric form, and/or its and/or the use of pharmaceutically acceptable solvates thereof. It is intended to provide a variety of services.

The present invention also provides treatment for hyperlipidemia, hypertension, cardiovascular disorders or certain eating disorders. Compounds of formula (+) for the preparation of therapeutic and/or prophylactic drugs; variant forms, and/or pharmaceutically acceptable salts thereof, and/or pharmaceutically acceptable salts thereof; Use of pharmaceutically acceptable solvates is provided.

For the compound represented by formula (1) in the above administration range, the toxicological effects are was not well established.

The following methods and examples are illustrative of the invention and are in no way limiting. It's not something you do.

Example 1 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth ethyl 3-(4-hyperoxy]phenyl]-2-methquinepropanoate under nitrogen atmosphere. dry ethyl droxyphenyl)-2-methoxypropanoate (2,38 g), Sodium hydride ( 60% dispersion in oil: 0.47 g) was added dropwise. The mixture was stirred at room temperature for 30 minutes. After that, 2-[N-(2-benzoxasilyl)-N-methylaminocoethanol Methanesulfonyl ester [European Patent Application Publication No. 0306228] (2 , 86 g) in N,N-dimethylformamide (90 mL) was added. Applicable The mixture was heated at 80° C. for 17 hours, then cooled and concentrated in vacuo. Water the residue (200 mL) and extracted with ethyl acetate (3X 200+aL). Match The organic solution was washed with water (3X 100mL), brine (200a+L), and dried. Drying (MgSOn) and evaporation gave a gum. This was used as an eluent. Chromatography on silica gel using Chrom01729 10% ethyl acetate The title compound was obtained in the form of a gum.

IHNMRδ(CD(J3) 1, 22 (3H, t): 2.95 (2H, composite): 3.33 (3H, s); 3.34 (3H.

s); 3.89 (IH, dd); 3.93 (2H, t): 4.17 (2H , Q); 4.24 (2H, t); 6.81 (2H, d): and 6.90-7 ．． 40 (6H, combined).

Example 2 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth xy]phenyl]-2-methokinopropanoic acid 3-[4-[2-[N-(2-benzoxasilyl)-N-methylaminocoeth ethyl xy]phenyl]-2-methoxypropanoate (1.5 g), 10% hydroxide A mixture of sodium aqueous solution (75μL) and methanol (23+1L) was heated to room temperature. Stir for 1.5 h, then dilute with water (600 mL) and dilute with dichloromethane (3 00++L) and acidified to pH 2 with concentrated hydrochloric acid. The mixture was diluted with ethyl acetate ( The combined ethyl acetate solution was extracted with water (2X 200mL). and brine (200 mL), dried (MgSC)a) and evaporated. . The residue was crystallized from ethyl acetate-dichloromethane-hexane to give the title compound. I got something. Melting point: 150-153°C.

IHNMRδ (CDC1,) 2.80 (LH, dd); 2.91 (IH, dd): 3.25 (3H, s) : 3.27 (3H.

s); 3.83 (LH, dd); 3.90 (2H, t): 4.22 (2H , t); 6.75-7°40 (8H, composite): and 12.60 (LH, bro (replaced with DzO).

Example 3 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Methyl phenylco-2-methquinepropanoate Method similar to that described in Example 1 Methyl 3-(4-hydroxyphenyl)-2-methquinopropanoate The title compound was prepared in the form of a gum.

IHNMRδ(CD(j,) 2.95 (2H, composite): 3.33 (3H, s) + 3.34 (3H, s); 3. 70 (3H.

s): 3.90 (3H, composite): 4.24 (2H, t); 6.80 (2H, d); and 7.00-7.40 (6H, combined).

Example 4 2-methquin-3-[4-[2-[N-methyl-N-(2-pyridyl)amino] Methyl ethquino]phenyl]propanoate 2-methquin-3-[4-[2-[N-methyl-N-(2-pyridyl)amino] Etquin]phenyl]propanonitrile (1.15g), sodium hydroxide solution (10% w/V; 10 mL) and methanol (20+ mL) was refluxed. The mixture was heated for 2.5 hours with stirring, then cooled and neutralized to pH 7 with dilute HCI. Applicable The mixture was evaporated in vacuo and the residue was dissolved in methanol presaturated with hydrogen chloride gas. Dissolved. The mixture was left at room temperature for 7 days and then evaporated. hydrogen carbonate Thorium saturated solution (100 mL) was added and the suspension was dissolved in ethyl acetate (3X200 mL).

Combined ethyl acetate solution in water (2X500++L) and brine (500mL) Washed with water, dried (MgSO4) and evaporated. The resulting gum-like substance is dichloromethane. Chromatography on silica gel using 1% methanol in lomethane The title compound was obtained in the form of a gum.

'HNMRδCCDCl5> 2.94 (2H, composite); 3.14 (3H, s) + 3.33 (3H, s); 3. 71 (3H.

s); 3.94 (LH, dd): 3.96 (2H, t); 4.15 (2H , t); 6.55 (2H9 composite) + 6.81 (2H, d) near, 11 (2H , d); 7.45 (IH, combined); and 8, 15 (IH, d d).

Example 5 3-[4-C2-[N-(2-benzoxasilyl)-N-methylamino]eth quino]phenylco-2-methoquino]propanamide 3-[4-[2-[N-(2 -benzoxasilyl)-N-methylamino]ethchin]-phenyl]-2-methane Methyl toxypropanoate (1,00g), tetrahydrofuran (20L), of tanol (20L) and ammonia aqueous solution (specific gravity 0.88:20+eL) The mixture was stirred at room temperature for 4 hours. Add further aqueous ammonia solution (20L) and continued stirring at room temperature for a total of 50 hours. The mixture was concentrated in vacuo and the residue was dissolved in water (5 00 mL) and extracted with ethyl acetate (3×200 mL). combined acetic acid The ethyl solution was washed with water (500 iL), brine (500 iL) and dried (M gSO3), evaporated. The residue was crystallized from dichloromethane-hexane. , the title compound was obtained. Melting point 133-5°C.

IHNMRδ (CDC/3) 2.88 (LH, dd); 3.07 (IH, dd): 3.33 (3H, s) ; 3.34 (3H.

s); 3.80 (IH, dd): 3.94 (2H, t); 4.24 (2H , t); 5.41 (IH, br, exchanged with D20); 6.33 (IH, br, D , exchanged with O); 6.80 (2H, d); 7,00 (IH, t); 7.13 ( 2H, d): 7.14 (LH, app, t); 7.25 (LH.

d): and 7.33 (LH, d).

Example 6 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl amino]ethoxy/]-phenyl]-2-ethoxypropanoate under nitrogen atmosphere , sodium hydride (60% fraction in oil: 0.33 g) in dry tetrahydrofuran (5aL) of triethyl 2-ethquinphosphonoacetate [double ・Grell & H.Machilate (W, Grell & H.

Machleidt), Annalen, Ch. emie), 1966.699.53 (1,98 g) of dry tetrahydrofura (25 L) solution was added slowly. The mixture was stirred at 0°C for 30 minutes. After that, 4-[2-[N-(2-benzoxasilyl)-N-methylamino]etheth xy]benzaldehyde (2.19 g) in dry tetrahydrofuran (15 ■ L) medium solution was added. The mixture was warmed to room temperature and stirred for a further 20 hours. solvent Evaporate and the residue is suspended in water (300 iL) and treated with ethyl acetate (3X 250a Extracted with L). The combined ethyl acetate layers were dissolved in water (2X IL) and brine (IL). Washed with water, dried (MgSCL) and evaporated.

The residue was purified on silica using 2.5% ethyl acetate in dichloromethane as eluent. Chromatography on gel produced a Z:E mixture of double bond isomers (62 :38) (according to 'HNMR integration of olefin signal). I got a compound.

IHNMRδ (CDC1z) 1.10-1.50 (6H, complex, isomer OCH*CHs jiggle (D mixture); 3.35 (3H,s, NMe); 3.85-4.30 (8H, complex, isomeric OCH x CHs O = ni: HiN CH1 dandan 20 signal mixture): 6.02 ( 0,38H”; s, E-olefin proton); 6.75-7.70 (8H, complex, isomeric aromatic protons); and 6.91 (0,62H”, s, Z-ole fin proton).

The two signals Hz together constitute the olefin proton signal. . The designation of the major isomer as Z (Z:E ratio is 62:38) is By similarity to the recorded chemical shifts of similar olefin protons [R. Aitken (R,A) and Tom (G) L. Thom), Synthesis, 1989.958 reference〕.

Example 7 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl amino]ethoxy]-phenyl]-2-phenoxypropenoate Example 6 Triethyl 2-phenoxyphosphonoacetate (0°94g) was added in the same manner as described. 4-[2-[N-(2-benzoxasilyl)-N-methylaminocoethoxy] 1:1 mixture of double bond isomers by reacting with benzaldehyde (0,89 g) The title compound was obtained (ratio determined by 'HNMR).

IHNMRδ (CDC1s) 5-4.30 (6H, complex, isomer 0 ICHI and NC, I, CH, O ): and 6.70-7.70 (14H, complex, aromatic and olefin signal).

Example 8 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth quin]phenyl]-2-phenoxypropanoate (E/Z)-3-44-[ 2-[N-(2-benzoxasilyl)-N-methiamino]ethquincophenyl ]-2-Phenoxypropenoic acid ethyl (0.97g) was dioxane (100iL ) and 10% palladium on charcoal (2 00 g). The solution was filtered through filter aid and evaporated. Residue The distillate was purified on silica gel using 5% ethyl acetate in dichloromethane as eluent. Chromatography above gave the title compound as a gum.

'HNMRδ (CDCl2) 1.18 (3H, t); 3.17 (2H, app d): 3.33 (3H, s); 3.93 (2H.

t); 4.13 (2H, q); 4.25 (2H, D; 4.71 (IH, dd) ; 6.81 (2H, d); and 6.90-7.40 (IIH, combined).

Example 9 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth [oxy]phenyl-2-phenoxypropanoic acid By a method similar to that described in Example 2, 3-[4-[2-[N-(2-benzo- xacylyl)-N-methylamino]ethoxy]phenyl]-2-phenoxypro From ethyl panate (0.88 g), the title compound with a melting point of 162-4°C (methanol) I got something.

'HNMRδ (DMSO-d,) 3, 10 (2H, composite); 3.21 (3H, s); 3.87 (2H, t): 4. 21 (2H.

t): 4.83 (LH, dd); 6.75-7.40 (13H, composite): and and 13.00 (replaced with IH, br, DtO).

Example 10 3-[4-[2-[N-(2-benzoxasilyl)-N-methylaminocoeth Methyl xy]phenyl]-2-ethoxypropanoate 3-[4-[2-[N-(2 -benzoxasilyl)-N-methylamino]ethoxycophenyl]-2-dia Methyl zopropanoate (2.80 g), ethanol (2.16 L) and benzene rhodium(II) acetate dimer (33 g) was added to a mixture of . The mixture was stirred for 15 minutes at room temperature under a nitrogen atmosphere and heated for an additional 1 hour at reflux. Heat for 5 minutes, then cool and evaporate in vacuo. The residue was diluted as an eluent. Chromatograph on silica gel using 1.5% methanol in lolomethane The title compound was obtained in the form of a gum.

IHNMRδ (CDCjs) 1.14 (3H, t); 2.93 (2H, app d); 3.31 (IH, composite): 3.32 (3H, S); 3.57 (LH, composite); 3.69 (3H, s) + 3.93 (3H, composite), 423 (2H, t); 6.79 (2 H, d); 7.00 (LH, t); 7.14 (3H, composite), 7°25 (LH , d): and 7.36 (LH, d).

Example 11 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Methyl xicophenyl]-2-isopropoxypropanoate Same as described in Example 1 3-(4-hydroxyphenyl)-2-isopropoxypropane by the method of The title compound was prepared in the form of a gum from methyl phosphate (1.34 g).

IHNMRδ (CDCI, ) 0.94 (3H, d); 1.13 (3H, d); 2.87 (2H, composite); 3 ．． 34 (3H.

s); 3.47 (LH, composite); 3.70 (3H, s); 3.93 (2H, t); 4.00 (IH, dd): 4.23 (2H, t); 6.79 (2H , d): 7.00 (IH, t); 7.17 (3H1 composite'): 7.25 ( IH, d); and 7.36 (IH, d).

Example 12 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Quincophenyl]-2-propoquinepropanoate methyl Same as described in Example 1 3-(4-hydroxyphenyl)-2-propoquine propanoic acid methyl The title compound was prepared as an oil from 0.88 g.

IHNMRδ (CDC/,) 0.83 (3H, t); 1.52 (2H, composite): 2.93 (2H, composite ); 3.17 (LH.

composite); 3.34 (3H, s): 3.50 (IH, composite); 3.69 (3H , s); 3.85-4.00 (3H, composite): 4.22 (2H, t); and 6 ．． 75-7.40 (8H, combined).

Example 13 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth [oxy]phenyl-2-propoxypropanoic acid By a method similar to that described in Example 2, 3-[4-[2-[N-(2-benzo- xacylyl)-N-methylaminocoethoxy]phenyl]-2-propoquinpro The title compound was prepared in the form of a gum from methyl panate (1.05 g). This substance is Used in the salt formation step without further purification.

IHNMRδ (CDCjs) 0.85 (3H, t); 1.53 (2H, t); 3.00 (2H, composite); 3.29 (IH.

composite): 3.32 (3H, s): 3.52 (IH, composite): 3.91 (2H, t ); 4.02 (LH, dd); 4.18 (2H, t); 5.80 (IH, br, (replaced with DzO); 6.77 (2H, d): and 6.95-740 (6H2 complex ).

Example 14 3-44-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Sodium salt of oxy]phenyl]-2-propoxypropanoic acid 3-[4-[2- [N-(2-Benzoxacylyl)-N-methylamino]ethoxy]phenylco - Stirring solution of 2-propoquine propanoic acid (0.81 g) in methanol (10 mL) Sodium methoxide (0.11 g) was added to the solution. After stirring for 5 minutes, the mixture The compound was evaporated and then reevaporated twice (10+eL each time) from ether.

The resulting gum is triturated with boiling ethyl acetate, filtered, and the filtrate is concentrated. diluted with ether. The resulting solid was filtered and dried in vacuo to yield the title compound. .

Melting point 210-4°C.

'HNMR6CDMSO-da) 0, 67 (3H, t); 1.35 (2H, composite); 2.65 (IH, dd) ;2.85 (IH.

dd); 3.02 (LH, composite): 3.25 (3H, s): 3.35 ( IH, composite); 3.70 (IH, dd): 3.90 (2H, t); 4.27 (2H, t); 6.80 (2H, d): and 7. OO-7,40 (6H, double ).

Example 15 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Amino]ethoxy]phenyl)-2-(4-methoxyphenoxy)propenoic acid ester Chill 2-(4-methquinphenoxy)phosphonoacetic acid in a manner similar to that described in Example 6. Triethyl acid (2,00 g) was converted into 4-[2-[N-(2-benzoxasilyl)- N-methylaminochoetquine]-benzaldehyde (1.71 g) , a 1.1 mixture of double bond isomers (ratio determined by 'HNMR). The following compound was obtained.

IHNMRδ (CDCI,) 1.08 and 1.19 (combined 3H, isomer 0CHtCHs triplet system) 3.32 and 3.34 (combined 3H,NMe singlet); 3 ．． 75 and 377 (combined 3H, OMe singlet): 3.95 (2H, composite)': 4.05-435 (4H, composite): 6.55 (0,5H, s, E-isomeric olefin proton); and 6.75-7.70 (12,5H, double ).

Example 16 3-[4-['2-[N-(2-benzoxasilyl)-N-methylamino]eth ethyl toxy]phenyl]-2-(4-methoxyphenoxy)propanoate solvent and (E/Z) by a method similar to that described in Example 8 using ethanol with -3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]ethyl From ethyl phenyl]-2-(4-methoxyphenoxy)propenoate to The title compound was obtained in the form of a cloud.

IHNMRδ (CDC1ri) 1, 18 (3H, t); 3.15 (2H1app, d); 3.33 (3H , S); 3.72 (3H.

s): 3.93 (2H, t); 4.15 (4H, composite): 4.62 (LH, t) ; 6.75 (4H, s); 6.81 (2H, d); and 6.95-7.40 (6H, composite).

Example 17 3-[4-[2-[N-(2-benzoxasilyl)-N-methinogemino]eth Description of Example 2 of xy]phenyl]-2-(4-methoxyphenoquino)propanoic acid 3-[4-[2-[N-(2-benzoxasilyl)- N-methylamino]ethyne]phenyl]-2-(4-methoxyphenoxy) From ethyl ropanate (1.62g), melting point 148-50℃ (methanol) The compound was obtained.

'HNMRδ(CDC1,) 3.20 (2H, d); 3.27 (3H, s): 3.71 (3H, s); 3.85 (2H, t) + 4.07 (2H, t); 4.72 (LH, t) + 6.7 0-7.30 (12H, combined), and 9.05 (IH, br, replaced with D20) .

Example 18 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl aminocoethoxy]phenyl-2-(4-methylphenoxy)propenoate By a method similar to that described in Example 6, 2-(4-methylphenoxy)phosphono The title compound, a 1.1 mixture of double bond isomers, was prepared from triethyl acetate. , obtained as a gum.

'HNMRδ (CDC1z) 1.07 and 1.19 (combined 3H, isomer 0CH2pHz tribletton 2.27 and 2.29 (combined 3H,Me singlet); 3. 31 and 3°34 (combined 3H, NMe signals): 3.90 (2H, combined ); 4.05-4.35 (4H1 composite); 6.64 (0,5H,s, E-O Lefin isomer): and 6.75-7°70 (12,5H, complex).

Example 19 (E/Z)-3-[4-[2-,[N-(2-benzoxasilyl)-N-methy ruamino]ethoxy]phenyl]-2-(4-methylphenoxy)propanoate By a method similar to that of Example 8, using ethanol as the chill solvent, (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl amino]ethoxy]phenyl]-2-(4-methylphenoxy)propenoate The title compound in the form of a gum was prepared from the solution.

IHNMRδ (CDC4) 1.18 (3H, s); 2.24 (3H, s); 3.15 (2H, composite); 3. 33 (3H.

s); 3.93 (2H, t); 4.17 (2H, Q); 4.23 (2H, t); 4.67 (IH.

t): 6.71 (2H, d); 6.81 (2H, d): and 6.95-7.4 0 (8H, composite).

Example 20 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth [Chin]phenyl]-2-(4-methylphenoxy)propanoic acid Description of Example 2 and By a similar method, 3-[4-[2-[N-(2-benzoxasilyl)-N -methylamino]ethoxy]phenyl]-2-(4-methylphenoquine)propyl The title compound was obtained from ethyl chloride with a melting point of 150-151 DEG C. (methanol).

'HNMRδ (CDC1s) 2.33 (3H, s); 3.21 (2H, d): 3.26 (3H, s); 3.84 (2H, t): 4.06 (2H, t); 4.77 (LH, t); 6 ．． 75 (4H, combined); 6.95-7.30 (8H, combined): and 7.35 ( (replaced with LH, br, DtO).

Example 21 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl amino]ethoxy]phenyl]-2-(2-methylphenoxy)propenoate 2-(2-methylphenoxy)phosphorus by a method similar to that described in Example 6. From triethyl acetate, the 44.56 ratio of double bond isomers (by 'HNMH) The title compound was obtained in the form of a gum.

IHNMRδ(CD(J’,) 1.06 and 1.14 (combined 3H, isomer OCR, Cdan, triplet series) ): 2.32 and 2.42 (combined 3H, methyl singlet); 3 ．． 31 and 3.34 (combined 3H,NMe singlet): 3.95 (2H , composite): 4.14 (2H1 composite); 4.26 (2H, composite); 6.48 ( 0,44H,E-olefin proton); 7.28(0,56H,Z-olefin proton); inproton): and 6.70-7.65 (12H, complex).

Example 22 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]etho Ethyl quincophenyl]-2-(2-methylphenoxy)propanoate as solvent (E/Z)-3 by a method similar to that described in Example 8 using ethanol -[4-C2-[N-(2-benzoxasilyl)-N-methylaminocoethyl] Gummy from ethyl [cy]phenyl]-2-(2-methylphenoxy)propenoate The title compound was prepared.

'HNMRδ (CDC13) 1.18 (3H, t) + 2.21 (3H, s): 3.18 (2H, d): 3.33 (3H, s); 3.93 (2H, t): 4.16 (2H, q): 4.23 (2H, t); 4.72 (LH, D: 6.57 (LH, d): and and 6.70-7.40 (IIH, combined).

Example 23 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth xy]phenyl]-2-(2-methylphenoquine)propanoic acid Description of Example 2 and By a similar method, 3-[4-[2-[N-(2-benzoxasilyl)-N -methylamino]ethoxycophenyl]-2-(2-methylphenoxy)propyl From ethyl chloride, the title compound with a melting point of 142-3°C (dichloromethane-hexane) I got it.

IHNMRδ (CDC4) 2.25 (3H, s); 3.25 (2H, d); 3.27 (3H, s): 3.83 (2H, t); 4.04 (2H, t); 4.82 (IH, t); 6.65-7.40 (12H, combined), and 7.88 (IH, br, DtO and exchange).

Example 24 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Methyl amino]ethoxy]phenyl]-2-(4-chlorophenoxy)propenoate 2-(4-chlorophenoxy)phosphonoacetic acid in a manner similar to that described in Example 6. Methyl diethyl is converted into 4-[2-[N-(2-benzoxasilyl)-N-methyla Minocoetoquine] is reacted with benzaldehyde to form a double bond of the gummy title compound. Obtained as a 1.1 mixture of polymers.

'HNMRδCCDCl5) 3.31 and 3.35 (combined 3H,NMe singlet); 3.65 and and 3°74 (combined 3H, OMe singlet); 3.93 (2H, combined ); 4.25 (2H.

and 6.70-7.70 (13H, composite); and 6.70-7.70 (13H, composite).

Example 25 3-[4-[2-[N-(2-benzoxasilyl)-N-mertylaminochoe] Methyl toquino]phenoquine]-2-(4-chlorophenoquino)propanoate at room temperature , (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methy [ruamino]ethquin]phenyl]-2-(4-chlorophenoquine)propenoic acid of iodine crystals dissolved in chill (0.98 g) and methanol (50 sL) Magnesium crumbs (0.5 g) were added to the mixture. The mixture is heated until the reaction occurs. Heat the mixture gradually using a heat gun, and when a reaction occurs, stop heating and remove the mixture. Additional magnesium (2,00 g) was added to the mixture for approximately 5 minutes while stirring at room temperature. and added. Place the reaction mixture in a cold water bath. ! Crush until all metal is dissolved Stirring was continued (~4 hours) and then the mixture was evaporated in vacuo. Water the residue (100 vL), and while stirring strongly, add monohydrochloric acid (until the suspension is completely After dissolution) a final pH of 1.5 was obtained. The mixture was diluted with ethyl acetate (2X100++ The combined ethyl acetate layers were extracted with water (500 sL) and brine (3 00sL), dried (MgSO,) and evaporated. The resulting gum on a glue gel using 3% ethyl acetate in dichloromethane as eluent. Chromatography gave the title compound, melting point 88-90°C.

'HNMRδ(CD CA'!,) 3.15 (2H, d): 3.33 (3H, s); 3.69 (3H, s); 3.93 (2H, t) + 4.23 (2H, t); 4.69 (IH, t): 6.73 (2H, d): 6.81 (2H, d), and 6.95-7.40 ( 8H, composite).

Example 26 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]etho /]phenyl]-2-(4-chlorophenoquino)propanoic acid and the description of Example 2 By a similar method, 3-[4-[2-[N-(2-benzoxasilyl)-N -methylamino]ethquin]phenyl]-2-(4-chlorophenoquine)propyl The title compound with a melting point of 164-5°C (methanol) was prepared from methyl phosphate.

IHNMRδ (CDC1g) 3.22 (2H, composite); 3.26 (3H, s); 3.84 (2H, non-decomposed t) :4.02 (2H1 non-decomposed t); 4.79 (LH, t); 6.75 (2H, d) ; 6.83 (2H, d); and 6.95-7.30 (9H, composite, one with D20); After shaking together, the temperature decreased to 8H).

Example 27 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth methyl xy]phenyl]-2-(phenylmethoxy)propanoate under nitrogen atmosphere, 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth methyl quino]phenyl]-2-hydroxypropanoate (1,20 g) in dry N, Sodium hydride (in mineral oil) was added to a stirred solution in N-dimethylformamide (20 sL). 60% dispersion; 0.14 g) was added dropwise. After stirring the mixture for 15 minutes at room temperature , benzyl bromide (0.6 mL) was added. 3 hours at room temperature, then 1 hour at 80°C. After continued stirring for 7 hours, the mixture was cooled, diluted with water (500 L), and diluted with acetic acid ethyl chloride. Extracted with chill (3X 200 mL). The combined ethyl acetate layers were diluted with water (4X 50 0sL) and saline (500+*L) and dried (Mg　Oa) , evaporated. The residue was purified with silica gel using 1% methanol in dichloromethane. Chromatography on a column gave the title compound in the form of a gum, which was further It was used in the next step without further purification.

'HNMRδ (CDC/3) 2.98 (2H, combined): 3.36 (3H, s); 3.70 (3H, s); 3.95 (2H.

t): 4.0? (IH, dd); 4.25 (2H, t); 4.35 (IH , d); 4.64 (LH, d); 6.80 (2H, d); and 6.9 5-7.45 (IIH, combined).

Example 28 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth [quin]phenyl]-2-(phenylmethquin)propanoic acid Same as described in Example 2 3-[4-[2-[N-(2-benzooxacylyl)-N-methane] thylaminochoetquin]phenyl]-2-(phenylmethquin)methypropanoate The title compound was prepared in the form of a foam. This material can be used without further purification. It was used as is in the salt formation step.

'HNMRδ (CDC1s) 3.00 (LH, dd): 3.10 (1)], dd): 3.32 (3H, s ): 3.90 (2H.

t) + 4.16 (3H, composite): 4.45 (IH, d) + 4.67 (I H, d); 4.75 (LH, broad, replaced with D20): '5.78 (2H, d ): and 6.95-7.45 (IIH1 complex).

Example 29 3-C4-[2-[N-(2-benzoxasilyl)-N-methyaminochoethoxy Sodium salt of nocophenyl]-2-(phenylmethokino)propanoic acid 3-[4 -[2-[N-(2-benzoxasilyl)-N-methylamino]ethquin]fluorocarbon Phenyl 3-2-(phenylmethoxy)propanoic acid (0.26 g) in methanol ( Sodium methoxide (0,031 g) was added to the stirred, water-cooled solution in 5 L).

The mixture was stirred at 0 °C for 10 min, then diluted with ether (10 sL) and evaporated. I let it emanate. Stir the residue and add ether (10 L each time) until a solid is obtained. It was re-evaporated several times. The solid was filtered from ether and dried under vacuum at 60°C for 1 week. This gave the title compound as a free-flowing powder.

'HNMRδ (DMSO-da) 2.67 (LH, dd); 2.90 (IH, dd); 3.23 (3H, s) ; 3.62 (IH.

dd): 3.88 (2H, t); 4.15 (IH, dd): 4.18 (2H , t); 4.63 (LH, d): 6.81 (2H, d): and 6.95-7. 45 (IIH, combined).

Example 30 (E/Z)-4-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl aminochoethochondrophenyl]-2-ethoxybut-2-enoate Example 6 4-[2-[N-(2-benzoxasilyl)- N-methylaminochoetquin] phenylethanal to obtain the title compound in the form of a gum. prepared and isolated as a mixture of 11 double bond isomers.

'HNMRδ (CDC13) 1.25-1.50 (6H, combined): 3.34 (3H, s): 3.50 (0 , 5x2H, d): 3.72 (2H, t); 3.90 (3H, composite): 4 ．． 20-4.35 (4H, combined), 5゜29 (0,5H, t) + 6.36 (0, 5H, t); 6.78 (2H, d); and 6.90-7.40 (6H, composite) .

Example 31 4-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Chin]phenyl]-2-ethynebutanoic acid (E /Z)-4-[4-[2-[N-(2-benzoxasilyl)-N-methiamino gummy The title compound was prepared.

'HNMRδ (CDC/3) 1.26 (6H, combined); 1.97 (2H, q); 2.68 (2H, combined) combination); 3.35 (3H.

s) + 3.37 (LH, composite); 3.63 (IH, composite): 3.75 (LH, t); 3.94 (2H, t); 4.15-4.25 (4H, composite) + 6.81 ( 2H, d): and 695-7.40 (6H, combined).

Example 32 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methia Ethyl minocoeto mushroom phenyl]-2-(2-naphthyloxy)propenoate Triethyl 2-naphthyloxyphosphonoacetate was prepared in a manner similar to that described in Example 6. -[2-[N-(2-benzoxasilyl)-N-methylamino]ethoxy]base Reaction with nzaldehyde gives the gummy title compound a 1.1 mixture of double bond isomers. It was isolated as a compound.

'HNMRδ(CD(J,) 1.02 Oyo U 1.15 (Ariseta 3 H; 0CH2CHs To’J’7 'l/-/tonk f-le): 3.27 and 3.33 (combined 3H:N Me singlet): 3.90 (2H, combined); 4.05-4.30 (4H, composite): and 6.75-7.80 (16H, composite).

Example 33 3-[4-[2-[N-(2-benzoxasilyl)-N-methyaminochoethoxy] Methyl nocophenyl]-2-(2-naphthyloxy)propanoate Example 25 (E/Z)-3-[4-[2-[N-(2-benzoyl)] was prepared by the same method as described above. xacylyl)-N-methylamino]ethoxy]phenyl]-2-(2-naphthyl The title compound was obtained in sticky form from ethyl oxy)propenoate.

IHNMRδ(CDCzs) 3.23 (2H, app d): 3.31 (3H, s): 3.70 (3H, s); 3.90 (2H.

t) + 4.21 (2H, t) + 4.91 (IH, dd): 6.81 (2H, d) : and 6.90-7.80 (13H, composite).

Example 34 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth xy]phenyl]-2-(2-naphthyloxy)propanoic acid Same as described in Example 2 3-[4-[2-[N-(2-benzoxasilyl)-N-methyl] Methyl amino]ethoxy]phenyl]-2-(2-naphthyloxy)propanoate The title compound was prepared from methanol, melting point 162-4°C (methanol).

'HNMRδ (DMSO-da) 3, 17 (2H, composite) + 3.19 (3H, s): 3.87 (2H, t); 4. 21 (2H.

t) + 5.03 (IH, dd) + 6.85 (2H, d) + 6.90-7.5 0 (IOH, composite) near, 72 (IH, d); 7.79 (2H, d): and 1 3.10 (replaced with IH, br, Dto).

Example 35 (Z)-2-ethquin-3-[4-[2-[N-methyl-N-(2-pyridyl) Aminochoet mushroom phenylcobropene ethyl ester dry tetrahydrofuran (25 Dissolve triethyl 2-ethoxyphosphonoacetate (3.44 g) in The solution was mixed with sodium hydride (60% dispersion in mineral oil; 0.56 g) under an argon atmosphere. ) was added slowly to a water-cooled, stirred suspension of 100% of the solution in tetrahydrofuran. The mixture was reduced to 0 After stirring for 30 min at °C, 4-[2-[N-methyl-N-(2-pyridyl)ami Etquincobenzaldehyde (European Patent Application Publication No. EP 0306228 ) (3.29 g) in tetrahydrofuran (30 liters) was added. the mixture The material was allowed to warm to room temperature over 22 hours with stirring and then concentrated in vacuo. residual The material was suspended in water (300 mL), extracted with ethyl acetate (2×300 mL), and combined. The combined ethyl acetate solution was washed with water (500 mL) and brine (500 mL). , dried (MgSO3) and evaporated. The gummy residue is extracted with hexane as eluent. Chromatography on silica gel using 20% ethyl acetate in The title compound was obtained as an oil.

Continuing the elution of the chromatography column, the isomer (E)-alkene (Example 3 6) to obtain a mixture consisting mostly of the (Z)-isomer.

IHNMRδ (CDC7′,) 1.35 (6H, t): 3.14 (3H, s) + 3.95 (4H, composite): 4.21 (2H.

t) +4.28 (2H, Q): 6.50 (2H, composite); 6.88 (2H, d); 6.95 (LH, s): 7.44 (LH, composite): 7.72 ( 2H, d); and 8.15 (IH, composite).

Example 36 (E)-2-Nidoquin-3-[4=[2-[N-methyl-N-(2-pyridyl) Chromatograph in ethyl amino]ethchin]phenyl]propenoate Example 35 The mixture of double bond isomers obtained from the Raffy column was eluted with Rechromatographed using 0% ethyl acetate. First, (Z)− Most of the isomers eluted, followed by the desired (E)-isomer as an oil.

'HNMRδ(CDCj's) 1.13 (3H, t): 1.40 (3H, t); 3.14 (3H, s); 3.90 (2H, q): 3.97 (2H, t); 4.15 (4H, combined) ; 6.06 (LH, s); 6.55 (2H.

composite): 6.81 (2H, d) near, 10 (2H, d) + 7.45 (IH, composite ): and 8°15 (LH, composite).

Example 37 3-[4-[2-[N-(2-benzoxasilyl)-N-methiamino]ethoxy methyl phenyl]-2-(2,2,2-trifluoroethoxy)propanoate By a method similar to that described in Example 1, 3-(4-hydroxyphenyl)-2- From methyl (2,2,2-trifluoroethoxy)propanoate, gummy marking I got a compound.

’HNMRδ(CD(J’s) 3.00 (2H, combined): 3.34 (3H, s): 3.65 (IH, combined) : 3.72 (3H.

s): 3.94 (2H1t): 4.00 (IH, combined) + 4.15 (IH, dd): 4.24 (2H, t): 6.81 (2H, d): and 6.95-7 ．． 40 (6H, combined).

Buy and sell analysis (FAB, glycerol) shows MH' at 453.1647.

[CzzHz! Theoretical value of FsNxOi 453.1637° Example 38 2-ethoxy-3-[4-[2-[N-methyl-N-(2-pyridyl)amino] Methyl ethoxy]phenyl]propanoate By a method similar to that described in Example 25, (Z)-2-nidoquine-3-[4-[ 2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]propyl The title compound was prepared in the form of a gum from ethyl chloride.

IHNMRδ (CDCI) 1.15 (3H, t): 2.93 (2H, d): 3.14 (3H, s): 3.3 3 (IH, combined): 3.56 (IH, combined) + 3.69 (3H, s); 3.95 (3H, composite); 4.15 (2H, t): 6.52 (2H, composite); 6.81 (2H, d); 7.11 (2H, d): 7.42 (LH, d t); and 8.13 (L H, d d).

Example 39 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Ethyl [xicophenyl]-2-ethoxypropanoate using ethanol as solvent Then, by a method similar to that described in Example 8, (E/Z)-3-[4-[2-[ N-(2-benzoxasilyl)-N-methylaminochoethochondrophenyl]- The title compound was prepared as an oil from ethyl 2-ethquinpropenoate.

'HNMRδ (CDC1s) 1, 15 (3H, t): 1.22 (3H, D; 2.92 (2H, d); 3. 33 (LH, combined); 3.34 (3H, s): 3.55 (IH, combined): 3.9 4 (3H, composite): 4.15 (2H, q); 4.24 (2H, t): 6.80 ( 2H,d); and 6.95-7.40 (6H1 complex).

Example 40 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth xy]phenyl]-2-ethoquinopropanoic acid By a method similar to that described in Example 2, 3-[4-[2-[N-(2-benzo- xacylyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropyl From ethyl ester, notation of melting point 109-110℃ (dichloromethane-hexane) A compound was produced.

'HNMRδ(CD(Js) 1.18 (3H, t) + 2.98 (IH, dd): 3.04 (LH, dd) ; 3.32 (3H.

s); 3.45 (LH, combined); 3.61 (IH, combined); 3.91 (2 H, t); 4.04 (IH, dd); 4.18 (2H, t); 5.0 (IH, br, replaced with DzO); 6.80 (2H, d); and 6.95-7.40 (6H, composite).

Example 41 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]etho oxy]phenyl]-2-nidoquine propanamide oxalyl chloride and 3-[4 -[2-[N-(2-benzoxasilyl)-N-methylamino]etkinkov A 1% solution of phenyl-2-ethoxypropanoic acid in dichloromethane (5 sL) It was refluxed for a while and then concentrated. Dissolve the residue in dichloromethane and add ammonia The mixture was stirred together with the aqueous solution for 30 minutes. After extraction with chloroform (x4), extract The material was dried and concentrated. Chromatography (diethyl ether/dichloromethane) A white foam was obtained which was crystallized from diethyl ether. melting point =94-95°C.

IHNMRδ (CDC13) 1.12 (3H, t, J = 7): 2.85 (IH, dd, J = 14.7.5); 3.07 (LH, dd, J-14, 3, 5); 3.35 (3H, s); 3. 37-3.55 (2H, m); 3°87 (IH, dd, J=7.5.3.5) : 3.94 (2H, t, J=5); 4.24 (2H.

tj=5): 5.54 (LH, br s): 6.43 (IH, br s); 6. 79 (2H.

d, J=8.5); 7.00 (IH, dt, J=8.1); 7.15 (2 H, d, J = 8.5) + 7.1-7.2 (LH, m) + 7.24 (LH, d d, J=8.1): 7.36 (LH, d.

J=8.1).

Example 42 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth quin]phenyl]-2-ethoquinotiopropanamide 3-[4-[2-CN-( 2-Benzoxalyl)-N-methylaminocoethoxy]phenylco-2-eth Xypropanamide (428 mg, 1,1 m+*ol) was suspended in toluene. Then Lawesson's reagent (1.1 eq.) was added. 3 hours later while returning to Japan , the suspension was cooled and poured into water. After extraction with chloroform (x3), extract was washed with aqueous ammonia, dried and concentrated. Chromatography (meta) ethanol/dichloromethane) to give the product as a white solid. Melting point 46- 48℃.

IHNMRδ (CDC43) 1.14 (3H, t, J=7); 2.91 (IH, dd, J=14.7); 3.25 (IH9dd, J=14.3); 3.35 (3H, s): 3.35-3 ．． 51 (2H, m); 3.94 (2H, tj=5); 4.24 (2H, t, J rhinoceros 5): 4.30 (IH, dd, J=7.3°5): 6.79 (2H, d, J=8.5): 7.01 (IH, appt, J=7.5); 7.16 (2H, d, J = 8.5); 7.13-7.2 (IH, obs, m) ; 7.25 (IH, d, J = 7°5); 7.35 (LH, d, J = 7.5 ); 7.44 (IH, br s); 7.72 (IH, br s).

Example 43 5-[2-[4-[2-[N-(2-benzoxasilyl)-N-methylamino ]Ethquine]phenyl]-1-ethochinoethyl-1,2,4-triazoledi 3-[4-[2-[N-(2-ben (zooxacylyl)-N-methylamibaethoxycophenyl-2-ethoxypro Panamide (0,562 g, 1.5 oL) was heated to 120 °C for 1% time, It was then cooled and concentrated. The residue was dissolved in acetic acid (4 sL) and then Radin hydrate (11 eq.) was added. After 1% hour at 100°C, cool the solution diluted with ethyl acetate and washed with water (x2) and sodium bicarbonate solution. . After drying and concentrating the solution, the residue was chromatographed (methanol/ dichloromethane) to give the product as a white solid. Melting point 127-129 ℃.

'HNMRδ(CD(J,) 1.13 (2H, t, J=7); 3.09 (2H, dq, J=16.6); 3.31 (3H.

s) + 3.46 (2H, q, J = 7) + 3.89-3.95 (2H, m); 4.20 (2H, t.

J = 5): 4.75 (LH, dd, J-6, 5, 5, 5); 6.72 (2H , d, J = 8.5); 6.96 (2H, d, J = 8.5): 7.0 1 (IH, dt, J=8.1) + 7.16 (LH.

dt, J = 8.1): 7.26 (IH, dd, J = 8.1): 7.33 (I H, dd, J=8゜1); 8. OO(IH,s).

Example 44 5-[2-[4-[2-[N-2-benzoxasilyl)-N-methylamino] ethoxy]phenyl]-1-ethoxyconityl-1,2,4-oxadiazole dimethylformamide dimethyl acetal [4-[2-[N-(2-benzooxy sacilyl)-N-methylaminochoetoquine]phenyl]-2-ethoquinepropane Amide (0.7 g, 1.8 Dragon 01) was heated to 120° C. for 1 hour each.

After cooling, the residue was concentrated and dissolved in 70% acetic acid aqueous solution (2C). 5N potassium hydroxide (0.44m) and hydroxylamine hydrochloride (15m) 2 mg) and then stirred for 15 minutes. After dilution with water, the reaction was Extracted with lolomethane (x2), washed the extract with water and dried (MgSOJ, Concentrated. This residue was dissolved in glacial acetic acid/dioxane (2/2 mL) for 1 hour. , heated to 90°C. After diluting with water, the product was extracted with chloroform (x3) The extract was washed with water (x2), dried and concentrated. chromatography (diethyl ether/hexane) to give the product as a yellow solid. melting point 89-90℃.

IH NMR δ (CDC43) 1, 16 (3H.t, J=7); 3.14 (IH.q, J=14); 3.1 8 (IH.qj=14); 3.34 (3H.s); 3.40-3.56 (2 H, m); 3.94 (2H.t.J=5): 4.23 (2H.t.J=5); 4, 75 (LH.dd.J=8.6); 6.79 (2H, a.J=9): 7. 00 (IH. dt, J=7.5.1): 7.07 (2H, d. J=9); 7. 16 (IH.d t. J=7.5.1); 7.31 (IH.dd , J=7.5.0. 5); 7, 35 (IH, dd.J=7.5.0.5): 8.37 (LH.s).

Example 45 Enantiomerically enhanced 3-[4-[2-[N-(2-benzoxasilyl) -N-methylaminochoetquin]phenyl]-2-methoxypropanoic acid methyl Rhizopus delemar-derived lipase ( 680mg, e.g. Biocatalys Ltd. ts Ltd)) in deionized water (380 L) and the pH of the mixture was adjusted to 7. ．． Adjusted to 0. The racemic form of 3-[4-[ 2-[N-(2-benzoxasilyl)-N-methylamino]ethoxy]pheny A solution of methyl]-2-methoxypropanoate (1 g) in acetone (20 mL) Added. The resulting reaction mixture was stirred and diluted with 0.1 M sodium hydroxide solution. The pH was maintained at 7.0 by automatic titration. 66% molar equivalents of base were added to the reaction. After the addition, hydrochloric acid was added to bring the solution to pH 2.0 and the product was dissolved in dichloromethane. extracted during the process. The organic phase was extracted with 50% saturated aqueous sodium bicarbonate solution and The reaction products were removed, washed with water, the organic phase was dried (magnesium sulfate) and evaporated. and has an enantiomeric ratio of 5:95 as determined by chiral HPLC assay. 3-[4-[2-[N-(2-benzoxasilyl)-N-methyl] 350 mg of methyl ruamino]ethoxy]phenyl]-2-methoxypropanoate Obtained. The basic aqueous extract was acidified by the addition of hydrochloric acid and reconstituted in dichloromethane. After extraction, drying and evaporation, 3-[4-[2-[N-(2-ben zoxasilyl)-N-methylamino]ethoxy]phenyl]-2-methoxyp Lopanic acid was obtained. This acid was dissolved in methanol presaturated with HCj for 3 hours at room temperature. stirring for a period of time, resulting in an enantiomeric ratio of 70:30 as determined by HPLC. 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino] Methyl ethchin]phenyl]-2-methoxypropanoate was recovered by extraction. .

3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth The enantiomeric ratio of methyl quinine]phenyl]-2-methquinepropanoate is chiral A 0, OIM sodium dihydrogen phosphate at pH 7.0 by HPLC on a GP column. Elution with 12% acetonitrile in solution and UV monitoring at 245 stops. It was determined by detecting the product. Enantiomeric ratios are set in order of elution. used.

Example 46 (+)-3-[4-[2-[N-(2-benzoxasilyl)-N-methylami Nocoetquin] phenyl] -2-methocinopropanoic acid Rhizopus prev - ( Lipase from Rhizopus delemar (300 mg, e.g. Io Catalysts Ltd.) in deionized water (125 L) and stir the mixture. The pH of the compound was adjusted to 7.0. Add 3-[4- (2-[N-(2-benzoxasilyl)-N-methylamino]ethoxy]phene methyl]-2-methoxypropanoate (produced in Example 1, enantiomeric ratio 8: A solution of 92) (690 mg) in acetone (:vL) was added. The resulting reaction mixture The mixture was stirred at room temperature and added with 0.1 M sodium hydroxide solution until the hydrolysis was complete. The pH was maintained at 7.0 by automatic titration. 0.1M sodium hydroxide solution The reaction mixture was brought to pH 9.5 by addition of dichloromethane and then washed with dichloromethane. Ta. The aqueous phase was acidified to pH 1 with hydrochloric acid and the acid was extracted into dichloromethane and washed. , dried (magnesium sulfate/rum) and evaporated. Combine the resulting solid with hexane (+)3-C4-[2-[N-(2-benzoxa silyl)-N-methylamino]ethochinophenylco-2-methquinepropanoic acid 490 mg was obtained: melting point 121-123°C, enantiomeric ratio 92:8 (HP by LC assay); [al,”+13°.MeOH.c O.5.3-[ 4-[2-rN-(2-benzoxasilyl)-N-methylamino]ethoquino] The enantiomeric ratio of phenyl]-2-methquine propanoic acid was determined on a chiral AGP column. HPLC at pH 7.0 and O. O 1M sodium dihydrogen phosphate solution Elute with 48% acetonitrile in solution and identify by UV monitoring at 245n It was measured by detecting the product. Enantiomeric ratios are quoted in order of elution. It will be done.

Example 47 (-)-3-[4-[2-[N-(2-benzoxasilyl)-N-methylami [Ethoxycophenyl]-2-methoxypropanoic acid Rhizopus pre7- (R lipase from Hizopus delemar (500 mg, e.g. Okiyatarists Ltd.) was stirred in deionized water (380 L) and the mixture The pH of the material was adjusted to 7.0. Add 3-[4-[ 2-[N-(2-Benzoxacylyl)-N-methylaminocoethoxy]phenylene ] = methyl 2-methquine propanoate (re-esterification of the acid produced in Example 1) (950 cg) in acetone (20 mL) was added. Ta. The resulting reaction mixture was stirred at room temperature and 32% molar equivalents of base were added to the reaction. pH 7.0 by automatic titration with 0.1 M sodium hydroxide solution until and then add hydrochloric acid to bring the solution to pH 2.0 and remove the product by dichloromethane. Extracted into lomethane. The organic phase was extracted with 50% saturated sodium bicarbonate solution. , remove the acid product, wash with water, dry the organic phase (magnesium sulfate/rum) and evaporate. In this way, 543 mg of recovered ester was obtained. The aqueous phase was acidified to pH 1 with hydrochloric acid and the chain acid was extracted into dichloromethane, washed, dried (magnesium sulfate) and evaporated. I set it. The resulting solid was triturated with hexane to give (-)3-[ as a white solid. 4-[2-[N-(2-Benzoxacylyl)-N-methylaminochoet mushroom 256 mg of phenyl]-2-methoxypropanoic acid were obtained; melting point 116-119°C. ; enantiomeric ratio 193 (by HPLC assay): [aln''-10''. Me OH. c　O. 55. Determination of enantiomeric ratios by HPLC was performed as described in Example 46. I followed.

Example 48 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl aminocoethoxy]-2-methquinophenyl]-2-ethquinpropenoate In a manner similar to that described in Example 6, triethyl 2-ethquinphosphonoacetate was converted to 4-[ 2-[N-(2-Benzoxacylyl)-N-methylamino]ethoxyco2- 66:34 mixture of double bond isomers by reacting with methquinobenzaldehyde The title compound in the form of a gum was obtained as a product.

’HNMRδ(CD(J’s) 1.09 and 1.25-1.45 (combined. 6H, OCH, CH31-rib Let): 3, 35 (3H, s): 3.75 and 3.80 (combined 3H , OMe’z glet): 3, 87-4.40 (8H, composite); 6.06 (0 , 34H, E-olefin nglets) and 6°40-8.18 (7,66 H, complex, aromatic protons and Z-olefins).

Example 49 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Ethyl quin]-2-methquinophenyl]-2-ethquinpropanoate Description of Example 8 (E/Z)-3-[4-[2-[N-(2-benzoxacyl)] lyl)-N-methylamino]ethkyne]-2-methquinphenyl]-2-ethoxy The title compound was prepared in the form of a gum from ethyl nopropenoate.

'HNMRδ (CDC1s) 1.10-1.40 (6H, combined): 2.94 (2H, combined); 3.34 (3H ,s); 3°35 (IH1 composite) + 3.55 (IH, composite); 3.76 (3H, s): 3.93 (2H, t); 4.10 (IH, dd) + 4.13 (2H, Q) : 4.24 (2H, t); 6.39 (2H, composite) and 6.95-7.40 ( 5H, composite).

Example 50 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl amino]ethoxycophenyl-2-tert-butquine propenoate Example In the same manner as described in 6, triethyl 2-tert-butquinphosphonoacetate was added to 4. -[2-[N-(2-benzoxasilyl)-N-methylamino]ethquin]ben 76:24 mixture of Z and E double bond isomers by reacting with nzaldehyde The title compound was obtained in the form of a gum.

IHNMRδ (CDC4) 118 and 1.35 (combined 3H, 0CH2C dan, tribrella tongual) .

127 and 1.34 (combined 9H, OBu' singlet); 3.34 and and 3°35 (combined 3H, NMe singlet); 3.95 (2H, combined): 4.10-4.28 (4H, composite): 6.53 (0,24H,s, E-olef 6.75-7.80 (8,76H, complex, Z-olefin and aromatic aromatic protons).

Example 51 3-[4-[2-[N-(2-benzoxasilyl)-N-methylaminocoeth Mushroom phenyl] Ethyl 2-tert-butoxypropanoate Description of Example 25 (E/Z)-3-[4-[2-[N-(2-benzooxy) sacilyl)-N-methylaminochoethochondrophenyl]-2-tert-buto The title compound was prepared in the form of a gum from ethyl quinpropeneate. This substance has a corresponding Although somewhat contaminated with methyl ester, the mixture was purified without further purification. It was used as is in the next step.

IHNMRδ (CDCl2) 0.91 (9H, s); 1.24 (3H, t); 2.85 (2H, composite); 3.34 (3H.

s): 3.93 (2H, t); 4.03 (IH, dd): 4.16 (2H , Q); 4.23 (2H, t): 6.79 (2H, d) and 6.95- 7.40 (6H, combined).

Example 52 3-[4-[2-[N-(2-benzoxasilyl)-N-methylaminocoeth Mushroom phenyl] 2-tert-butquinopropanoic acid Same as described in Example 2 Depending on the method, 3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl ruaminochoetochoshinophenyl]-2-tert-butquine propanoate The title compound was prepared in the form of a gum.

'HNMRδ (CDCrx) 1.04 (9H, s): 2.84 (IH, dd): 2.98 (LH, dd) ; 3.34 (3H.

s): 3.93 (2H, t); 4.13 (IH, dd) + 4.21 (2H , t); 6.79 (2H, d): 6.95-7.40 (6H, composite) and 7 ．． 45 (IH, broad, replaced with D20).

Example 53 3-[4-[2-[N-(2-benzoxasilyl)-N-methylaminocoeth mushroom phenyl]-2-tert-butquine propanoic acid sodium salt 3-[4 -[2-[N-(2-benzoxasilyl)-N-methylamino]ethoxy]fluoride methanol ( Sodium hydride (60% dispersion in mineral oil, 50 mg ) was added. The mixture was stirred at 0 °C for 10 min, concentrated in vacuo, then diluted with diethyl Rediluted with ether (40 mL). The resulting solid was filtered and dried to obtain the standard The following compound was obtained. Melting point>250℃.

IHNMRδ (DMSOds) 0, 85 (9H, s); 2.43 (IH, dd); 2.73 (IH, dd ): 3.21 (3H.

s): 3.55 (LH, dd): 3.86 (2H, t); 4.19 (2H , t): 6.77 (2H, d) and 6.95-7.40 (6H, composite).

Example 54 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl amino]ethoxycophenyl]-2-(2-phenylethquin)propenoate 2-(2-phenylethoquine) phosphorus by a method similar to that described in Example 6. from triethyl acetate, labeled as a Z,E mixture (71:29) of double bond isomers. The following compound was obtained.

IHNMRδ (CDC7s) 114 and 1.34 (combined 3H, 0CH2CHs tribrella tonnal ).

3.05 (2H, combined): 3.33 and 334 (combined 3H, NMe signal ), 3°95-4.30 (8H, composite): 6.07 (0,298, E-ole Fin Nombre Yt] and 6.70-7.55 (13,71H, composite, Z- olefins and aromatic protons).

Example 55 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Methyl xicophenyl]-2-(2-phenylethoxy)propanoate Example 25 (E/Z)-3-[4-[2-[N-(2-ben zooxacylyl)-N-methylamino]ethquino]phenyl]-2-(2-phenyl) The title compound was obtained in the form of a gum from ethyl propenoate.

IHNMRδ (CDCI,) 2.84 (2H, t) + 2.93 (2H, composite); 3.34 (3H, s) ; 3.43 (IH.

composite) + 3.68 (3H, s) + 3.77 (IH, composite); 3.94 (3H, composite) ); 4.23 (2H, t); 6.77 (2H, d) and 6.95-7.4 0 (IIH, combined).

Example 56 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Quin]phenyl]-2-(2-phenylethoquino)propanoic acid Description of Example 2 and By a similar method, 3-[4-[2-[N-(2-benzoxasilyl)-N -methylamino]ethquine]phenyl]-2-(2-phenylethoquine)propyl From methyl chloride, the title compound with melting point 131-36C (dichloromethane-hexane) I got something.

'HNMRδ (CDCI) 2.85 (2H, D; 2.93 (IH, dd); 3.04 (IH, dd) ; 3.32 (3H.

S); 3.57 (LH, combined); 3.77 (IH, combined); 3.91 (2H, t); 4.02 (LH, dd): 4.17 (2H, D; 6.10 (IH, dd); load, replaced with D20); 6.77 (2H, d) and 6.95-7.40 (I IH, composite).

Example 57 (E/Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ethyl amino]ethoxy/]phenyl]-2-(2-methoxyethoxy)propenoate 2-(2-methoxyethoxy)phosphor by a method similar to that described in Example 6. from triethyl acetate as a Z, E mixture of double bond isomers (76:24) The title compound was obtained in the form of a gum.

IHNMRδCCDCl5) 1.12 and 1.35 (combined 3H, 0CH2CH3 triblet); 3.3 5-3°45 (combined 6H1 composite NMe and OMe singlet); 3. 67 and 3.72 (combined 2H, complex, OCH, CH, ○Me signals): 3.90-4.35 (8H.

composite): 6.15 (0,24H,E-olefin nonblet) and 6.80 -7.8 (1 (8,76H, composite).

Example 58 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Methyl xicophenyl]-2'-(2-methquinethoquine)propanoate Example 2 (E/Z)-3-[4-[2-[N-(2-beta)] by the same method as described in 5. nzoxazinol)-N-methylamino]ethoxy]phenyl]-2-(2-methyl The title compound in the form of a gum was prepared from ethyl (toquinoetoquine)propenoate.

'HNMRδ (CDC4) 2.95 (2H, composite); 3.29 (3H, s); 3.34 (3H, s): 3.47 (3H.

composite); 3.68 (IH, composite): 3.69 (3H, s); 3.93 (2H, t ); 4.06 (IH, dd); 4.23 (2H, t): 6.79 (2H, d) and and 6.95-7.40 (6H1 composite).

Example 59 (Z)-3-[4-[2-[N-(2-benzoxasilyl)-N-methylami Methyl hydrogen [nocoetochinophenyl]-2-(carboxymethocino)propenoate (60% dispersion in mineral oil, 0.30 g), dimethyl diglycolate ( 0.81 g) and 4-[2-[N-(2-benzoxasilyl)-N-methyl amine]ethquine]benzaldehyde (2.22 g) in dry benzene (50 mL) ) The warm mixture was stirred at room temperature overnight. Acetic acid (1 mL) was added and the mixture was diluted with ice water. Pour on top and extract with ethyl acetate. The combined ethyl acetate layers were washed with water and dried. (MgSO4) and evaporated. The obtained ura is mixed with 2292% methanol The product was chromatographed on Nori gel using an acetic acid solution. Crystallized from chill. Melting point 111-112°C.

'HNMRδ (CDCA3) 3.34 (3H, s); 3.83 (3H, s): 3.95 (2H, t): 4.25 (2H, t): 4.51 (2H, s): 6.85-7.50 (9H, double combination) and 9.40 (exchanged with LH, Broad, D, O).

Example 60 3-[4-[2-4N-(2-benzoxasilyl)-N-methylamino]eth Methyl quincophenyl]-2-(carboxymethquine)propanoate Example 8 (Z)-3-[4-[2-[N-(2-benzoxa silyl)-N-methylamino]ethoxy]phenyl]-2-(carpoquinmethoxy) /) The title compound was prepared from methyl propenoate, melting point 154-155°C.

IHNMRδ (CDC4) 2.95 (IH, dd); 3.09 (LH, dd); 3.31 (3H, s) ; 3.75 (3H.

S); 3.93 (2H, combined); 4.07 (2H, s); 4.20 (3H, composite); 6.79 (2H, d) and 6.95-7.40 (7H, ?j [combined,] :hO and KI:tidecrease to 16H).

Example 61 5-[2-[4-[2-[N-(2-benzoxasilyl)-N-methylamino ]Ethoquino]phenyl]-1-ethyquinethyl-3-methyl-1,2,4-o Xadiazole N,N-dimethyl instead of N,N-dimethylformamide dimethyl acecool In a similar manner as described in Example 44 using acetamido dimethyl acecool , the title compound was prepared, melting point 61-62°C.

IHNMRδ (CD Cz,) 1.15 (3H, t): 2.39 (3H, s): 3.12 (IH, q); 3.14 (LH, q): 3.35 (3H, s): 3.35-3.60 (2H , m); 3.94 (2H, t); 4.23 (2H, t) + 4.65 (LH , dd); 6.79 (2H, d) and 7. OO-7,36 (6H1 composite) .

Example 62 5-[2-[4-[N-(2-benzoxasilyl)-N-methylaminocoeth Mushroom phenyl]-1-ethquinethyl]-1,2,3,4-(IH)-tet Lazole 3-[4-[2-[N-(2-benzoxasilyl)-N-methylami Nocoethquin]phenyl]-2-ethquinpropanonitrile (0.85g) of N , sodium anhydride (0,7 6 g) and trimethylmonlyl chloride (1+*L) were added. the mixture for 4 days Reflux, cool, pour into water and extract with ethyl acetate. Combined ethyl acetate layers Washed with water, dried and evaporated. Using 1% methanol in ether as solvent. Purify the residue by chromatography on silica gel using The title compound was obtained as a white foam.

IHNMRδ (CDC13) 1.13 (3H, t); 3.12 (2H, dd); 3.22 (3H, s); 3 ．． 51 (2H.

dq): 3.88 (2H, t): 4.15-4.20 (2H, m); 4.99 (LH, t) + 6゜22 (2H, d) + 6.80 (2H, d); 7 ．． 04 (IHdt); 7.16 (LH, dt) and 7.25-7.31 (2H ’, m).

Method 1 3-(4-hydroxyphenyl)-2-methokinopropanoate ethyl acetate (II) dimer (10+ag), methanol (7.9 mL) and benzene (5 0 L) of 2-diazo-3-(4-hydroxyphenyl)propylene into the stirred refluxing mixture. Ethyl panate [N, Takamura and T. Mizogu] TMizoguchi, Tetrahedron Letters on Lett, ), 1971.4495] (8,8 g) of benzene (40 m L) solution was added over 30 minutes.

The mixture was heated at reflux for a further 30 minutes and then cooled to room temperature overnight. and washed with water (2×200 mL). Dry the benzene solution (MgSO4) , evaporate the residual oil, first using 20% ethyl acetate in hexane as eluent. , then chromatographed on silica gel using dichloromethane 94% ethyl acetate. Graphing twice gave the title compound as an oil.

'HNMRδ (CDC1s) 1.22 (3H, t); 2.94 (2H, d); 3.35 (3H, s): 3.94 (IH, t); 4.20 (2H, q); 5.73 (LH, DzO and Exchange): 6.75 (2H, d); and 7, 15 (2H, d).

Method 2 Methyl 3-(4-hydroxyphenyl)-2-methoxypropanoate under nitrogen atmosphere , rhodium(11) acetate dimer (0.18 g) in methanol (50 mL) at room temperature. ) methyl 2-diazo-3-(4-hydroxyphenyl)propanoate [ See Tetrahedron Letters, 1971.4495. The solution in ethanol (120 L) was added over 10 minutes. Reflux the resulting mixture Heat for 5 hours with stirring, then stand at room temperature for 15 hours, then concentrate in vacuo. Ta. Dissolve the residue in ethyl acetate (500 L) and water (3X 300 S+L) and brine (500 L), dried (MgSO4) and evaporated.

The resulting gum was dissolved in ethyl acetate-6% acetic acid in dichloromethane as eluent. Chromatography on silica gel using a gradient of ethyl gave the title The compound was obtained. Melting point 61-3°C.

'HNMRδ (CDCI,) 2.95 (2H, d); 3.40 (3H, S) + 3.75 (3H, s): 4.00 (IH, t) Method 3 (E/Z)-1-methoxy-2-[4-[2-[N-methyl-N-(2-pyridi )amino]ethochinocoffenyl]ethenemethokinomethyltriphenylphosphor Dissolve nium chloride (12.34 g) in dry tetrahydrofuran (200 L). lithium neuisopropylene, cooled to -10°C, and stirred under nitrogen atmosphere. solution of Ruamide (2.0M+ in heptane/tetrahydrofuran/ethylbenzene) 13.5 mL) was added over approximately 5 minutes. The resulting mixture was heated to 10°C, Stirred at this temperature for 1 hour. At 10°C, 4-[2-[N-methyl-N-(2-pi lysyl) aminochoetquin] benzaldehyde [European Patent Application Publication No. 030 6228] (4.60 g) in dry tetrahydrofuran (75 mL). and the mixture was stirred at room temperature for 465 hours.

The solvent was evaporated and the residue was dissolved in water (600 L) and dichloromethane (3x 250oL). Add the combined dichloromethane solution to water (3X IL) and and brine (IL), dried (MgS　4) and evaporated. residual The material was purified on silica gel using 15% methanol in dichloromethane as eluent. chromatography at , a gummy mixture of 11 double bond isomers The title compound was obtained.

'HNMRδ (CDCl, ) (Z)-Alkene 3.12(3H,s)+3.72(3H,s):3.94( 2H, t) + 4.14 (2H, t); 5.14 (LH, d, J = 7.0Hz) ; 6.01 (IH, d, J = 7°0Hz): 6.48 (2H, combined): 6 ．． 80 (2H, d); 7.11 (2H, d); 7.45 (IH2 composite): and 8.15 (IH, dd).

(E)-Alkene 3.12(3H,s); 3.63(3H,s); 3.94( 2H, t); 4.15 (2H, t); 5.74 (IH, d, J-12,9Hz) :6.49 (2H, composite); 6.80 (2H, d); 6.88 (LH, d, J= 12.9Hz): 7.45 (3H, combined); and 8.15 (IH, dd).

Method 4 1.1-dimethoquino 2-[4-[2-[N-methyl-N-(2-pyridyl)a Mino]ethoxy/]-phenyl]ethane (E/Z)-1-methoxy-2-[4-[2-[N-methyl-N-(2-pyridi (2.80 g), p-toluenesulfonate A mixture of phosphoric acid-hydrate (1.90 g) and methanol (150 IIL) was refluxed. Heated with flowing water for 20.75 hours, then cooled and evaporated. vinegar residue Dissolve in ethyl acid (200 L) and add saturated sodium bicarbonate solution (200 L). ) and brine (200 cL), dried (MgSO4) and evaporated. . The title compound in the form of a gum was used in the next step without purification.

'HNMRδ (CDC7,) 2.85 (2H, d) + 3.15 (3H, s): 3.33 (6H, s); 3.98 (2H, t): 4.20 (2H, t): 4.49 (IH, t); 6.5 0-7.50 (7H, combined), and 8.20 (I H, d d).

Method 5 2-methoxy/-3-[4-[2-[N-methyl-N-(2-pyridyl)amino] Ethomushroom-phenyl] phlobanonitrile At room temperature, 1,1-dimethoquino-2-[4-['2-[N-methyl-N-(2-pi lysyl)aminochoetquin]phenyl]ethane (2,64g) in dichloromethane Trimethyluranide (3.4 L) was added dropwise to the solution in (70+IL).

Boron trifluoride-ether complex compound (0.3 L) was added while stirring the mixture. and continued stirring at room temperature for 15 hours, then added boron trifluoride-ether. The tel complex compound (1 L) was added. After a further 2 hours, the mixture was dichloromethane (100 L), saturated sodium bicarbonate solution (2 x 300 L), Washed with water (2x300sL) and saline (300sL), dried (MgS O4) was evaporated. The residue was dissolved in 1% methanol in dichloromethane as 1 u. Chromatography on silica gel gave the title compound in the form of a gum. was obtained and used without further purification.

IHNMRδ (CDCI) 3,04(2H,d); 3.14(,3)H,s); 3.46(3H,s ); 3.96 (2H, t); 4.16 (3H, composite) + 6.5’5 ( 2H, composite): 6.48 (2H, d): 7.15 (2H.

d): 7.45 (IH, t d): and 8.15 (IH, d d).

Method 6 2-amino-3-[4-[2-[N-(2-benzoxasilyl)-N-methyl amine]ethquino]phenyl]methyl propanoate under nitrogen atmosphere, thyronone methyl Ester (3,90 g) in dry N,N-dimethylformamide (70 IIL) Add sodium hydride (60% dispersion in oil) to the stirred solution.

1,00g) was added dropwise. After stirring the mixture for 30 minutes at room temperature, 2-[N-( 2-benzoxasilyl)-N-methyaminocoethanol methanesulfonyl ester Dry N, N - solution in dimethylformamide (30 mL) was added. The mixture was heated at 100°C. Heat for 6 hours, cool, dilute with ice water (500 WL) and dilute with ethyl acetate (3X250 WL). mL). The combined ethyl acetate layers were washed with brine (2xlL) and dried. (MgSO4) and evaporated. The residue was purified with dichloromethane 95% as eluent. % methanol on silica gel. this Crystallization from ethyl acetate gave the title compound, mp 95-6°C.

IHNMRδ (CD CA3) 1.45 (2H, br, replaced with DzO); 2.81 (LH, dd); 3.01 ( LH, dd) + 3.33 (3H, s): 3.67 (LH, dd): 3.7 0 (3H, s); 3.95 (2H.

t); 4.25 (2H, t); 6.83 (2H, d), and 6.95-7 ．． 40 (6H, combined).

Method 7 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Methyl xy]phenyl]-2-diazopropanoate 2-amino-3-[4-[2- [N-(2-Benzoxacylyl)-N-methylamino]ethquin]phenyl] Methyl propanoate (5,OOg), acetic acid (4,4+aL) and chloroform ( A mixture of 160+aL) was treated dropwise with isoamyl nitrite (3.2 mL).

The mixture was heated at reflux for 1.5 hours, then cooled and dissolved in chloroform ( diluted with diluted hydrochloric acid (200 l), water (2X 200 vl) and It was washed continuously with saline solution (200 L). Dry the chloroform solution with Mg5O, Dry, evaporate and then dissolve the residue in dichloromethane 93% acetic acid as eluent. Chromatography on silica gel using ethyl gives a gummy label. The following compound was obtained.

IHNMRδ(CDCz, ) 3.34 (3H, s); 3.56 (2H, s): 3.77 (3H, s); 3.94 (2H, t); 4.25 (2H, t); and 6.80-7.40 (8H, composite).

Method 8 Methyl 3-(4-hydroxyphenyl)-2-isopropoxypropanoate Method 2 2-diazo-3-(4-hydroxyphenyl)propylene was prepared by a method similar to that described in The title compound was prepared in the form of a gum from methyl lopanoate (3,00 g).

'HNMRδ (CDC/3) 0.97 (3H, d) + 1.14 (3H, d); 2.91 (2H, composite): 3.51 (LH.

composite); 3.71 (3H, s) + 4.05 (IH, dd); 6.02 (I H, br, replaced with DzO): 6.75 (2H, d); and 7.08 (2H , d).

Method 9 Methyl 3-(4-hydroxyphenyl)-2-propoquine propanoate Description of Method 2 2-noacy3-(4-hydroxyphenyl)propyl The title compound was prepared as an oil from methyl phosphate (2.56 g).

IHNMRδ (CDC13) 0.83 (3H, t): 1.54 (2H, composite) + 2.93 (2H, ap p, d); 3.22 (IH9 composite): 3.51 (IH, composite): 3. 71 (3H, s): 3.99 (IH, t): 5.54 (IH, br, intersecting with DzO ), 6.74 (2H, d): and 7.08 (2H, d).

Methyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate nitrogen atmosphere Bottom, ice-cold suspension of 10% palladium on charcoal (1.90 g) in methanol (30 mL) Add methyl 3-(4-pennyloxyphenyl)-2-hydroxypropanoate to the solution [ International Patent Application Publication No. WO9101337] (5,72g) of methanol (1 20 IIL) solution was added. Add solid ammonium formate (6.4 g) , the mixture was heated at reflux for 15 minutes, then cooled to room temperature. diatomaceous earth The catalyst was removed by filtering the reaction mixture through and the solvent was evaporated.

The residue was suspended in dilute hydrochloric acid (2M, 10QmL) and ethyl acetate (2X400aL) ) was extracted. The combined ethyl acetate solution was mixed with water (400 L) and saline solution (400 L). *L), dried (MgSO4) and evaporated. The obtained gum-like substance, on silica gel using 1,5% methanol in dichloromethane as eluent. Chromatography gave the title compound, melting point 42-43°C.

'HNMRd (CDC13) 2.85 (LH, l'o　)', replaced with DzO); 2.90 (LH, dd): 3 ．． 05 (LH, dd) + 3.77 (3H, s); 4.42 (IH, m, D2 Disintegrated into dd after washing with 0); 5.36 (IH, broad, crossed with D20 10); 6.70(2H,d)I and 7.05(2H,d).

Method 11 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth Methyl quincophenylco-2-hydroquinopropanoate Same as described in Example 1 Methyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate The title compound with a melting point of 109-112°C was prepared from the solution.

'HNMRd　(CD(Js) 2.68 (IH, d, replaced with DiO): 2.90 (LH, dd); 3.05 (L H, dd); 3.35 (3H, s); 3.76 (3H, s): 3.95 (2 H, t); 4.25 (2H, t): 4.41 (LH, m, ]: d after washing with ho decay into d); 6.81. (2H, d); and 6°95-7.40 (6H, composite).

Method 12 2-[4-[2-[N-(2-benzoxasilyl)-N-methylaminocoeth Methyl quincophenylcoethanoate Methyl 4-hydroxyphenylethanate (8.30 g) at room temperature under nitrogen atmosphere. To a stirred solution of sodium hydride in dry N,N-dimethylformamide (10C15L) (60% dispersion in mineral oil, 2.20 g) was added dropwise. the mixture at this temperature After stirring for 30 minutes, 2-[N-(2-benzoxasilyl)-N-methylamino N,N-dimethyl of nocoethanol methanesulfonyl ester (13,50g) A solution in formamide (15 (bL)) was added. The mixture was heated at 80°C for 18 hours. Heat, then cool and concentrate in vacuo. The residue was diluted with water (IL) and treated with acetic acid ethyl chloride. The combined ethyl acetate solution was extracted with water (4x IL). ), washed with brine (IL), dried (MgSO3) and evaporated. residue on silica gel using 1.5% methanol in dichloromethane as solvent. Chromatography yields the title compound in the form of a gum, which must be further purified. I used it without.

'HNMRδ (CDC43) 3.35 (3H, s); 3.57 (2H, s); 3.70 (3H, s); 3.93 (2H, t): 4.28 (2H, t); and 6.85-7.45 (8H, composite).

Method 13 2-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth quin]phenyl]ethanol Lithium aluminum hydride (1.36 g) in ether (50 m L) 2-[4-[2-[N-(2-benzoxasilyl) -N-methylaminocoethoxycophenyl]methyl ethanoate (11.60g) A solution in dry diethyl ether (200 mL) was added slowly. the mixture Stir at 0°C for 20 minutes, then add water (10+aL) and hydrochloric acid (2M: 10m L) was carefully added dropwise. Dilute the mixture with water (200 mL) and adjust the solution to pH 4 and then extracted with ethyl acetate (3×200 eL). combined ethyl acetate water (2 x 5001IL), saline solution (500wL), wash L, dry m sasse (MgSO4), evaporated to give the title compound, melting point 95-97°C.

'HNMRδ (CDC13) 2.15 (IH, bu o-F, exchanged with DzO) + 2.75 (2H, t): 3. 30 (3H, s); 3.80 (2H, t); 3.97 (2H, t); 4.22 ( 2H, t); and 6.80-7.45 (8H, combined).

Method 14 4-[2-[N-(2-benzoxasilyl)-N-methylamino]ethoxy] Phenylethanal Under nitrogen atmosphere, 2-[4-[2-[N-(2-benzoxasilyl)-N-methyl Ruaminochoetquin]phenyl]ethanol (1,00g), triethylamine (2.25 vL) and dichloromethane (3 QmL) was added to a stirred water-cooled mixture of Dimethyl sulfoquinide (5 mL) of gin-sulfur trioxide complex compound (1,53 g) medium solution was added. The mixture was stirred at 0°C for 10 minutes, then at room temperature for 5 hours. After that, it was diluted with dichloromethane (100 mL), water (2X100+aL), hydrochloric acid ( 0,5M+100+iL), water (2X100mL) and saline (100mL) '1' washed, dried (MgSO3) and evaporated. The residue was diluted as a solvent. Chromatography on silica gel using 5% ethyl acetate in chloromethane The title compound was obtained in the form of a gum.

IHNMRδ (CDC4) 3.29 (3H, s): 3.53 (2H, d); 3.86 (2H, t); 4.19 (2H, t) + 6.80-7.50 (8H, composite): and 9.68 (LH, t).

Method 15 3-(4-hydroxyphenyl)-2-(2,2,2-)lifluoroethquino) Methyl propanoate Rhodium(II) acetate dimer (0,064 g) and 2 , 2゜To a stirred mixture of 2-trifluoroethanol (5 vL) was added 2-diazo-3 2.2.2 of methyl -(4-hydroxyfernyl)propanoate (3,OOg) - Add the solution in trifluoroethanol (10 mL) slowly over 15 minutes. did. The mixture was stirred at room temperature for 15 minutes and then heated at reflux for 4 hours. , then cooled and evaporated. The residue was dissolved in 4% ethyl acetate in tsukukoromethane. chromatography on silica gel to obtain the title compound in the form of a gum. was obtained and used without further purification.

IHNMRδ(CD(Js) 3.00 (2H, combined); 3.65 (LH, combined); 3.74 (3H, s); 4 ．． 00(LH.

composite) +4.17 (IH, dd): 5.20 (IH, blow 1', Dioto exchange); 6.75 (2H, d): and 7.08 (2H, d).

Mass spectrometry (El) shows M''' at 278.0763 amu: Cl2H13 Theoretical value of F301・278.0766° Method 16 3-[4-[2-[N-(2-benzoxasilyl)-N-methylamino]eth quin]phenylco-2-ethoxypropanonitrile 4-[2-[N-(2-ben zooxacylyl)-N-methylaminocoethoxy]phenylethanal (1,5 g), p-toluenesulfonic acid-hydrate (100a+g), 3A molecular A mixture of sorb (2 g) and ethanol (30 mL) was heated at 18:00 under reflux. The mixture was heated for 30 minutes, then cooled and stirred with potassium carbonate (5 g) for 30 minutes.

The mixture was filtered through Celite and evaporated to give 3-[4-[2-[N-(2 -benzoxasilyl)-N-methylamino]ethchin]phenylcoethanal Diethylacecool was obtained and was used without further purification (below).

Dilution of the acetal (15 g) and trimethyluranide (0.5 g) Boron trifluoride-ether complex in chloromethane (20IIL) midstream (4℃) solution Compound (0,05+eL) was added. The mixture was warmed to room temperature and stirred for 24 hours. After that, it was poured into an aqueous sodium hydrogen carbonate solution. The organic phase was separated and dried (M gSOs) and then evaporated. The residual oil was dissolved in dichloromethane as eluent. Chromatographed on silica gel using 0% ether as an oil. The title compound was obtained.

'HNMRδ(CDC/,) 1.20 (3H, t): 3.05 (2H, d): 3.30 (3H, s); 3.3 -4.8 (2H1 composite) + 3.87 (2H, t); 4.10-4.30 (3 H, composite): 6.82 (2H, d) and 6.90-7.40 (6H, composite) .

Demonstration of compound efficacy Obese rats, oral glucose tolerance test C57bll/6 oblob mice were fed a powdered oxoid diet.

After at least one week, continue to feed the rat with powdered oxoid diet, or A powdered oxoid diet containing the test compound was fed. After 8 days of supplementary feeding, mice All animals were fed for 5 hours before oral administration of glucose (3 g/kg).

0145.90 and 135 minutes after glucose administration for glucose analysis A blood sample is taken and the results are expressed as a percent reduction in the area under the blood glucose curve and tested. The compound treated group was compared to the control group. Eight rats were used for each treatment. used.

table Table (continued) International investigation report Roll LC mouth @ ttn + x Take 1 Continuation of front page (51 month comparison C1,6 identification symbol 8 internal reference number C07D239/42 Z86 15-4C2631589283-4C 413/12 = 249 7602-4C2577602-4C 2637602-4C (31) Priority claim number 9311027.8 (32) Priority mill May 1993 28th (33) Priority claim country: United Kingdom (GB) FI (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE) , 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE , S.N.

TD, TG), AT, AU, BB, BG, BR, CA.

CH, CZ, DE, DK, ES, FI, GB, HU, JP, KP, KR, KZ, LK, LU, MG, MN, MW, NL, No, NZ, PL, PT, RO, RU, S.D.

SE, SK, UA, US, VN (72) Inventor: Syme, John Thomas, United Kingdom, Lee R.H. 3. 7 Agea, Betchworth, Brodscombe Park (no address displayed) Smith Klein Beecham Pharmaceuticals

Claims (25)

[Claims] 1. Formula (I); A1-X-(CH2)m-O-A2-A3-YR2(I) [wherein, A1 represents a substituted or unsubstituted aromatic heterocyclic group, and A2 optionally represents 3 groups. represents a benzene ring which may have a substituent, and A3 is of the formula -(CH2)m-C Represents a group represented by H(OR1)-, where R1 is a substituted or unsubstituted atom. represents alkyl, aryl, aralkyl or alkylcarbonyl, m is 1 to 5 or A3 represents an integer in the range of or A3 has the formula -(CH2)m-1-CH=C( represents a group represented by OR1)-, where R1 and m are the same as defined above; the law of nature; R2 represents OR3, where R3 is hydrogen, alkyl, aryl or ara or R2 represents an aromatic heterocyclic group or -NR4R5. where R4 and R5 are each independently hydrogen, alkyl or alkyl. or R4 and R5 represent the nitrogen radicals to which they are attached. together with its children to form a heterocycle, provided that Y represents a bond as defined below. R2 represents an aromatic heterocyclic group; X represents NR, where R is a hydrogen atom, an alkyl group, an acyl group, an aryl an aralkyl group in which the moiety may be substituted or unsubstituted, or a substituted or represents an unsubstituted aryl group; Y represents CO or CS or a bond, provided that R2 is the above aromatic heterocyclic group only when representing, Y represents a bond; n represents an integer in the range of 2 to 6] or its tautomeric form, and/or its pharmaceutically acceptable form. and/or pharmaceutically acceptable solvates thereof. 2. Al has formula (a), (b) or (c); ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (b) ▲ There are mathematical formulas, chemical formulas, tables, etc. (c) [wherein R6 and R7 are each independently hydrogen or halogen] atoms, alkyl or alkoxy groups, or substituted or unsubstituted aryl groups. or when R6 and R7 are each bonded to adjacent carbon atoms, R6 and R7 are , together with the carbon atoms to which they are attached, form a benzene ring, where: The carbon atoms represented by R6 and R7 together are substituted or unsubstituted, X1 in the group represented by formula (a) represents oxygen or sulfur] 2. A compound according to claim 1, wherein 3. Claim 1 or earlier, wherein A3 represents a group represented by the formula -(CH2)m-CH(OR1)- or the compound described in 2. 4. Claim 1 or 2, wherein A3 represents a group represented by the formula -CH=C(OR1)- compound. 5. R1 is substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl 4. A compound according to any one of claims 1 to 3. 6. Any of claims 1 to 5, wherein R1 is unsubstituted alkyl or unsubstituted aralkyl. The compound according to item 1. 7. The compound according to any one of claims 1 to 6, wherein R1 is ethyl or benzyl. thing. 8. 8. A compound according to any one of claims 1 to 7, wherein R2 represents OR3. 9. 9. A compound according to claim 8, wherein R3 represents hydrogen or alkyl. 10. 10. The compound according to claim 1, wherein m is 1 and n is 2. 11. A compound as described in any one of Examples 1 to 62 described in the specification, or tautomeric forms thereof, and/or pharmaceutically acceptable salts thereof, and/or or a pharmaceutically acceptable hydrate thereof. 12. a) Formula (II); R■-A2-A3'-Y. R2'(II) [wherein A2 and Y are in formula (I) A3 is represented by the formula -(CH2)m-CH(OR1')-. where R1' is R1 defined in formula (I) or its represents the protected form, m is the same as defined in formula (I), or A3 represents a group represented by the formula -(CH2)m-1-CH=C(OR1')-, where and R1' is the same as defined above; R2' is R defined in formula (I). 2 or its protected form, Ra is the formula (f); A1-X-(CH2)n-O-(f) (wherein A1, X and n are the same as defined in formula (I)) [is a group that can be converted into] A compound represented by is reacted with an appropriate reagent capable of converting Ra to group (f). b) Formula (I) in which A3 represents a group represented by the formula -(CH2)m-CH(OR1)- ) Formula (VII); ▲ Numerical formula, chemical formula, table, etc. ▼(VII) [wherein A1, A2, X, Y, m and n are in formula (II) and R9 is the same as the definition in formula (IV)]. The activated form of the compound represented by formula (VIII); R1-L1(VIII) [wherein R1 is the same as defined in formula (I), L1 is a leaving group or a radical Represents a child] React with a compound represented by; c) In formula (I) in which A3 represents a group represented by the formula -(CH2)m-CH(OR1)- For the preparation of the compounds shown, formula (x); A1-X-(CH2)m-O-A2-(CH2)m-C-Y-R9(X) [in the formula , A1, A2, X, Y, m and n are the same as defined in formula (I), and R 9 is the same as the definition in formula (IV)] The carbene source represented by the above definition d) A3 is of the formula -(CH2)m-1-C Represents a group represented by H=C(OR1)- or -(CH2)m-CH(OR1)- For the production of a compound of formula (I), formula (XII); A1-X-(CH 2) m-O-A2-(CH2)m-1-CHO(XII) [wherein A1, A2, X, m and n are the same as defined in formula (I)], From the CHO carbon atom to the formula CH=C(OR1)-Y. To the group represented by R2 and then, optionally, the group -CH=C(OR1 )- is reduced, and A3 represents a group represented by the formula -(CH2)m-CHOR1 get something; e) A3 represents a group represented by the formula -CH2-CH(OR1)-, where R1 is Regarding the production of a compound represented by formula (I) representing alkyl, formula (XV); A1- X-(CH2)n-O-A2-CH2-CH(OR1)-CN(XV) [wherein, A1, A2, R1, X and n are the same as defined in formula (I)] hydrolyzing the compound represented by the formula (I) in which R2 represents OH, R2 as OH is then optionally converted to another R2; f) A3 is converted to (C H2) m-CH(OR1)-, and R2 is a C-bonded aromatic heterocyclic group; Regarding the production of the compound represented by (I), the compound represented by formula (XII) as defined above A compound of formula (XX); ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XX) [In the formula, het-CH is at least is also an aromatic heterocyclic group represented by R2 containing one carbon atom] and then react the compound in which R1 is hydrogen with the activated form of the compound represented by Convert to another R1; 9) A3 is (CH2)m-CH(OR1)- and R2 is C-bonded tetrazolyte Regarding the production of a compound represented by formula (I) which is a group, formula (XXI): ▲ Formula, There are chemical formulas, tables, etc. ▼ (XXI) [In the formula, A1, A2, R1, X, m and n is the same as defined in formula (I)]. Any azide ion source and preferably an alkali such as e.g. sodium azide. Reacting in metal azide: then optionally the following optional steps: (i) A step of converting a compound represented by formula (I) into another compound represented by formula (I); (ii) removing any protecting groups: and (iii) represented by formula (I) Pharmaceutically acceptable salts of compounds and/or pharmaceutically acceptable solvates thereof represented by formula (I), characterized in that one or more of the steps for producing or its tautomeric form, and/or its pharmaceutically acceptable A method for producing a salt and/or a pharmaceutically acceptable hydrate thereof. 13. Conversion of a compound represented by formula (I) to another compound represented by formula (I) a) converting the group R into another group R; b) converting the group OR1 into another group OR1 c) a group Y. where Y is CO; If R2 is replaced by another group Y. Converting to R2: d ) Group CO. R2 with another group CS. and e) the group -CH=C Claim 12 comprising reducing (OR1)- to the group -CH2-CH(OR1) Manufacturing method described. 14. A group Y. where Y is CO. from R2 to another group Y. The conversion to R2 is (i) R2a is The group Y. is alkyl, aryl or aralkyl. R2a is a group Y where Y is CO ．． (ii) the group Y. in which R2b is alkoxy; R2b is a group Y. where Y is CO. Aminating NR4R5: (iii) Group Y of the above definition. Halogenating OH to form the corresponding acid halide and then amination of the halide to form the above group Y. where Y is CO. N.R. Obtaining 4R5; (iv) The group YOH is alkylated or aralkylated to form a group Y, in which Y is CO. (v) obtaining a group Y. where Y is CO; NH2, Y-C-Het, where Y is a bond and C-Het is a C-bonded aromatic heterocyclic group; 14. The manufacturing method according to claim 13, comprising converting. 15. Rhizopus delemar, Rhizopus delemar Rhizopus arrhizus, Rhizop us) LIP F4-derived lipase or Mucor m. one enantiomeric ester group CO2Z using lipase derived from enantioselectively hydrolyzed to carboxyl groups and then, optionally, enantiomers The product carboxylic acid that is enriched in the carboxylic acid or the substrate ester that is enantiomerically enriched Formula (H), which is characterized by separation; ▲There are mathematical formulas, chemical formulas, tables, etc.▼(H) [Wherein, Cx is a chiral carbon, Z is a C1-12 alkyl group, and Z1 is C1-12 alkyl, aryl or arylC1-12 alkyl group ] for separating optical isomers of a compound (substrate ester) consisting of a group represented by Method. 16. A3 represents (CH2)m-CH(OR1)-, Y represents CO, and R2 OR3, and A1, A2, R1, R3, X, m and n are Compounds enriched in certain enantiomers of formula (I) as defined by formula (I) ( (hereinafter referred to as the compound represented by formula (IA)), or its tautomeric forms, and and/or a pharmaceutically acceptable salt thereof, and/or a pharmaceutically acceptable salt thereof. Solvate. 17. a compound of formula (IA) according to claim 18 in optically pure form; or tautomeric forms thereof, and/or pharmaceutically acceptable salts thereof, and/or or a pharmaceutically acceptable solvate thereof. 18. A compound of formula (I), or its tautomeric form, or its pharmaceutical or its pharmaceutically acceptable solvates and its pharmaceutically acceptable salts, or pharmaceutically acceptable solvates thereof; 1. A pharmaceutical composition comprising a carrier that can be used as a carrier. 19. Compounds of formula (I), or tautomers thereof, useful as active therapeutic substances isomeric forms, and/or pharmaceutically acceptable salts thereof, and/or pharmaceuticals thereof -acceptable solvates. 20. of formula (I) useful in the treatment and/or prevention of hyperglycemia a compound, or a tautomeric form thereof, and/or a pharmaceutically acceptable salt thereof; and/or a pharmaceutically acceptable solvate thereof. 21. Treatment of hyperlipidemia, hypertension, cardiovascular disease and certain eating disorders and/or or a compound of formula (I), or a tautomer thereof, useful in prophylaxis form, and/or its pharmaceutically acceptable salts, and/or its pharmaceutically acceptable salts. Acceptable solvates. 22. Hyperglycemic human or non-human mammals in need of treatment and/or prophylaxis A compound of formula (I), or its tautomeric form, and/or its Non-toxic pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates thereof hyperemia in a human or non-human mammal, characterized by administering an effective amount of A method for treating and/or preventing diabetes. 23. A compound of formula (I) to a human or non-human mammal in need of treatment. , or tautomeric forms thereof, and/or pharmaceutically acceptable salts thereof, and and/or administering a non-toxic effective amount of a pharmaceutically acceptable solvate thereof. hyperlipidemia, hypertension, cardiovascular disease in humans or non-human mammals. and methods of treating certain eating disorders. 24. of formula (I) for the manufacture of a drug for the treatment and/or prevention of hyperglycemia. or tautomeric forms thereof, and/or pharmaceutically acceptable salts thereof. , and/or the use of pharmaceutically acceptable solvates thereof. 25. Treatment of hyperlipidemia, hypertension, cardiovascular disease or certain eating disorders and / or a compound of formula (I) or a tautomer thereof for the manufacture of a prophylactic drug sex form, and/or its pharmaceutically acceptable salts, and/or its pharmaceutically acceptable salts. Use of solvates allowed in.